Macrocyclic compounds as IRAK1/4 inhibitors and uses thereof

ABSTRACT

The present invention relates to compounds of Formula I and pharmaceutically acceptable compositions thereof, useful as IRAK inhibitors.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.62/112,374, filed on Feb. 5, 2015, the entire contents of which arehereby incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention provides for compounds of Formula (I) as IRAKinhibitors and their use in the treatment of cancer, and other diseasesrelated to IRAK overexpression, including rheumatoid arthritis, systemiclupus erythematosus or lupus nephritis.

BACKGROUND OF THE INVENTION

Kinases catalyze the phosphorylation of proteins, lipids, sugars,nucleosides and other cellular metabolites and play key roles in allaspects of eukaryotic cell physiology. Especially, protein kinases andlipid kinases participate in the signaling events which control theactivation, growth, differentiation and survival of cells in response toextracellular mediators or stimuli such as growth factors, cytokines orchemokines. In general, protein kinases are classified in two groups,those that preferentially phosphorylate tyrosine residues and those thatpreferentially phosphorylate serine and/or threonine residues.

Kinases are important therapeutic targets for the development ofanti-inflammatory drugs (Cohen, 2009. Current Opinion in Cell Biology21, 1-8), for example kinases that are involved in the orchestration ofadaptive and innate immune responses. Kinase targets of particularinterest are members of the IRAK family.

The interleukin-1 receptor-associated kinases (IRAKs) are criticallyinvolved in the regulation of intracellular signaling networkscontrolling inflammation (Ringwood and Li, 2008. Cytokine 42, 1-7).IRAKs are expressed in many cell types and can mediate signals fromvarious cell receptors including toll-like receptors (TLRs). IRAK4 isthought to be the initial protein kinase activated downstream of theinterleukin-1 (IL-1) receptor and all toll-like-receptors (TLRs) exceptTLR3, and initiates signaling in the innate immune system via the rapidactivation of IRAK1 and slower activation of IRAK2. IRAK1 was firstidentified through biochemical purification of the IL-1 dependent kinaseactivity that co-immunoprecipitates with the IL-1 type 1 receptor (Caoet al., 1996. Science 271(5252): 1128-31). IRAK2 was identified by thesearch of the human expressed sequence tag (EST) database for sequenceshomologous to IRAKI (Muzio et al., 1997. Science 278(5343): 1612-5).IRAK3 (also called IRAKM) was identified using a murine EST sequenceencoding a polypeptide with significant homology to IRAK1 to screen ahuman phytohemagglutinin-activated peripheral blood leukocyte (PBL) cDNAlibrary (Wesche et al., 1999. J. Biol. Chem. 274(27): 19403-10). IRAK4was identified by database searching for IRAK-like sequences and PCR ofa universal cDNA library (Li et al., 2002. Proc. Natl. Acad. Sci. USA99(8):5567-5572).

Mice that express a catalytically inactive mutant of IRAK4 instead ofthe wild-type kinase are completely resistant to septic shock triggeredby several TLR agonists and are impaired in their response to IL-1.Children who lack IRAK4 activity due to a genetic defect suffer fromrecurring infection by pyogenic bacteria. It appears that IRAK-dependentTLRs and IL-1Rs are vital for childhood immunity against some pyogenicbacteria but play a redundant role in protective immunity to mostinfections in adults. Therefore IRAK4 inhibitors may be useful for thetreatment of chronic inflammatory diseases in adults without making themtoo susceptible to bacterial and viral infections (Cohen, 2009. CurrentOpinion in Cell Biology 21, 1-8). Potent IRAK4 inhibitors have beendeveloped (Buckley et al., 2008. Bioorg Med Chem Lett. 18(12):3656-60).IRAK1 is essential for the TLR7-mediated and TLR9-mediated activation ofIRF7 and the production of interferon-alpha (IFN-α) suggesting thatIRAK1 inhibitors may be useful for the treatment of Systemic lupuserythematosus (SLE). IRAK2 is activated downstream of IRAK4 and plays arole in proinflammatory cytokine production. Therefore IRAK2 inhibitorsmay be useful for inflammatory diseases.

SUMMARY OF THE INVENTION

In one aspect, the invention provides compounds of Formula (I):

and pharmaceutically acceptable derivatives, solvates, salts, hydratesand stereoisomers thereof.

In another aspect, the invention provides compounds of Formula (I) whichare suitable for the treatment and/or prevention of disorders related toIRAK1 and IRAK4. In another aspect, the invention provides compoundswhich are able to modulate, especially inhibit the activity or functionof IRAK1 and IRAK4 in disease states in mammals.

According to another aspect the invention provides methods for thetreatment and/or prevention of disorders selected from auto-immune,inflammatory disorders, cardiovascular diseases, neurodegenerativedisorders, bacterial and viral infections, allergy, asthma,pancreatitis, multi-organ failure, kidney diseases, plateletaggregation, cancer, transplantation, sperm motility, erythrocytedeficiency, graft rejection, lung injuries, respiratory diseases andischemic conditions.

In certain embodiments, the present invention provides compounds ofFormula (I) which are selective for IRAK-4 and/or IRAK-1. In certainembodiments, the present invention provides compounds of Formula (I)which are selective for IRAK-4 and IRAK-1.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCompounds of the Invention

In certain aspects, the present invention provides for inhibitors ofIRAK. In some embodiments, such compounds include those of the formulaedescribed herein, or a pharmaceutically acceptable salt thereof, whereineach variable is as defined and described herein.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Exemplary aliphatic groups are linear or branched, substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl groups andhybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, orphosphorus (including, any oxidized form of nitrogen, sulfur, orphosphorus; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

According to the invention, bivalent groups include substitution in bothdirections, and when inserted between any two groups, (e.g., the group“—OC(O)—” or “CO₂” inserted between X and Y), includes both

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic andbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains three to seven ring members. The term “aryl”is used interchangeably with the term “aryl ring”. In certainembodiments of the present invention, “aryl” refers to an aromatic ringsystem. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyland the like, which optionally includes one or more substituents. Alsoincluded within the scope of the term “aryl”, as it is used herein, is agroup in which an aromatic ring is fused to one or more non-aromaticrings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group is optionally mono- or bicyclic. The term “heteroaryl”is used interchangeably with the terms “heteroaryl ring”, “heteroarylgroup”, or “heteroaromatic”, any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl),or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclicgroup”, “heterocyclic moiety”, and “heterocyclic radical”, are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group is optionally mono- or bicyclic.The term “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, certain compounds of the invention contain“optionally substituted” moieties. In general, the term “substituted”,whether preceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. “Substituted” applies to one or more hydrogens that areeither explicit or implicit from the structure (e.g.,

refers to at least

refers to at least

Unless otherwise indicated, an “optionally substituted” group has asuitable substituent at each substitutable position of the group, andwhen more than one position in any given structure is substituted withmore than one substituent selected from a specified group, thesubstituent is either the same or different at every position.Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable”, as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently deuterium; halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which are optionallysubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₁Ph which is optionallysubstituted with R^(∘); —CH═CHPh, which is optionally substituted withR^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which is optionally substituted withR^(∘); —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘), SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘),—(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂;—N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straightor branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight orbranched)alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) is optionallysubstituted as defined below and is independently hydrogen, C₁₋₆aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), ora 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which is optionally substituted as definedbelow.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently deuterium, halogen, —(CH₂)₀₋₂R^(•),-(haloR^(•)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂;—O(haloR^(•)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH,—(CH₂)₀₋₂C(O)OR^(•), —(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂,—(CH₂)₀₋₂NHR^(•), —(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —C(O)SR^(•),—(C₁₋₄ straight or branched alkylene)C(O)OR^(•), or —SSR^(•) whereineach R^(•) is unsubstituted or where preceded by “halo” is substitutedonly with one or more halogens, and is independently selected from C₁₋₄aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which is substituted as defined below, oran unsubstituted 5-6-membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which is optionally substitutedas defined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which is optionallysubstituted as defined below, unsubstituted —OPh, or an unsubstituted5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain embodiments, the terms “optionally substituted”, “optionallysubstituted alkyl,” “optionally substituted “optionally substitutedalkenyl,” “optionally substituted alkynyl”, “optionally substitutedcarbocyclic,” “optionally substituted aryl”, “optionally substitutedheteroaryl,” “optionally substituted heterocyclic,” and any otheroptionally substituted group as used herein, refer to groups that aresubstituted or unsubstituted by independent replacement of one, two, orthree or more of the hydrogen atoms thereon with typical substituentsincluding, but not limited to:

—F, —Cl, —Br, —I, deuterium,

—OH, protected hydroxy, alkoxy, oxo, thiooxo,

—NO₂, —CN, CF₃, N₃,

—NH₂, protected amino, —NH alkyl, —NH alkenyl, —NH alkynyl, —NHcycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocyclic, -dialkylamino,-diarylamino, -diheteroarylamino,

—O— alkyl, —O— alkenyl, —O— alkynyl, —O— cycloalkyl, —O-aryl,—O-heteroaryl, —O— heterocyclic,

—C(O)— alkyl, —C(O)— alkenyl, —C(O)— alkynyl, —C(O)— carbocyclyl,—C(O)-aryl, —C(O)— heteroaryl, —C(O)-heterocyclyl,

—CONH₂, —CONH— alkyl, —CONH— alkenyl, —CONH— alkynyl, —CONH—carbocyclyl, —CONH-aryl, —CONH-heteroaryl, —CONH-heterocyclyl,

—OCO₂— alkyl, —OCO₂— alkenyl, —OCO₂— alkynyl, —OCO₂— carbocyclyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocyclyl, —OCONH₂, —OCONH—alkyl, —OCONH— alkenyl, —OCONH— alkynyl, —OCONH— carbocyclyl, —OCONH—aryl, —OCONH— heteroaryl, —OCONH— heterocyclyl,

—NHC(O)— alkyl, —NHC(O)— alkenyl, —NHC(O)— alkynyl, —NHC(O)—carbocyclyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocyclyl,—NHCO₂— alkyl, —NHCO₂— alkenyl, —NHCO₂— alkynyl, —NHCO₂— carbocyclyl,—NHCO₂— aryl, —NHCO₂— heteroaryl, —NHCO₂— heterocyclyl, —NHC(O)NH₂,—NHC(O)NH— alkyl, —NHC(O)NH— alkenyl, —NHC(O)NH— alkenyl, —NHC(O)NH—carbocyclyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH—heterocyclyl, NHC(S)NH₂, —NHC(S)NH— alkyl, —NHC(S)NH— alkenyl,—NHC(S)NH— alkynyl, —NHC(S)NH— carbocyclyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocyclyl, —NHC(NH)NH₂, —NHC(NH)NH—alkyl, —NHC(NH)NH— -alkenyl, —NHC(NH)NH— alkenyl, —NHC(NH)NH—carbocyclyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH—heterocyclyl, —NHC(NH)— alkyl, —NHC(NH)— alkenyl, —NHC(NH)— alkenyl,—NHC(NH)— carbocyclyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl, —NHC(NH)—heterocyclyl,

—C(NH)NH— alkyl, —C(NH)NH— alkenyl, —C(NH)NH— alkynyl, —C(NH)NH—carbocyclyl, —C(NH)NH— aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocyclyl,

—S(O)— alkyl, —S(O)— alkenyl, —S(O)— alkynyl, —S(O)— carbocyclyl,—S(O)-aryl, —S(O)— heteroaryl, —S(O)— heterocyclyl —SO₂NH₂, —SO₂NH—alkyl, —SO₂NH— alkenyl, —SO₂NH— alkynyl, —SO₂NH— carbocyclyl, —SO₂NH—aryl, —SO₂NH— heteroaryl, —SO₂NH— heterocyclyl,

—NHSO₂— alkyl, —NHSO₂— alkenyl, —NHSO₂— alkynyl, —NHSO₂— carbocyclyl,—NHSO₂— aryl, —NHSO₂-heteroaryl, —NHSO₂-heterocyclyl,

—CH₂NH₂, —CH₂SO₂CH₃,

-mono-, di-, or tri-alkyl silyl,

-alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl,-heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic,-heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy,-methoxyethoxy, —SH, —S— alkyl, —S— alkenyl, —S— alkynyl, —S—carbocyclyl, —S— aryl, —S-heteroaryl, —S-heterocyclyl, ormethylthiomethyl.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. In some embodiments, the groupcomprises one or more deuterium atoms.

Deuterium (²H) can also be incorporated into a compound of the formula Ifor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus causes a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a compoundof the formula I that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art is able to optimize pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula I with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula I are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concentration at maximum therapeutic effect(C_(max)), area under the dose response curve (AUC), and F; and in termsof reduced clearance, dose and materials costs.

As used herein, the term “modulator” is defined as a compound that bindsto and/or inhibits the target with measurable affinity. In certainembodiments, a modulator has an IC₅₀ and/or binding constant of lessabout 50 μM, less than about 1 μM, less than about 500 nM, less thanabout 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in IRAK activity between a samplecomprising a compound of the present invention, or composition thereof,and IRAK, and an equivalent sample comprising IRAK, in the absence ofsaid compound, or composition thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

3. Description of Exemplary Compounds

According to one aspect, the present invention provides a compound offormula I,

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is a 5-membered heterocylic ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or a    5-membered monocyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur; each of    which is optionally substituted;-   Ring B is a 6-membered aryl, or a 6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted;-   Ring C is a 5-membered heterocylic ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or a    5-membered monocyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur; each of    which is optionally substituted;-   X is absent, —CH═CH—, —C≡C—, —O—, —S—, —SO₂—, —SO—, —C(O)—, —CO₂—,    —C(O)N(R)—, —OC(O)N(R)—, —NRC(O)—, —NRC(O)N(R)—, —NRSO₂—, or —N(R)—;-   Y is absent, a divalent C₃₋₁₀ aryl, a divalent 3-8 membered    saturated or partially unsaturated carbocyclic ring, a divalent 3-7    membered heterocylic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or a divalent 5-6    membered monocyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur; each of    which is optionally substituted;-   each R is independently hydrogen, C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8    membered saturated or partially unsaturated carbocyclic ring, a 3-7    membered heterocylic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur; each of which is    optionally substituted; or-   each R is independently —OR^(c), —SR^(c), —SO₂R^(c), —SOR^(c),    —C(O)R^(c), —CO₂R^(c), —C(O)N(R)R^(c), —OC(O)N(R)R^(c),    —NRC(O)R^(c), —NRC(O)N(R)R^(c), —NRSO₂R^(c), or —N(R)R^(c);-   two R groups on the same atom are taken together with the atom to    which they are attached to form a C₃₋₁₀ aryl, a 3-8 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted;-   R^(a) is H or optionally substituted C₁₋₆ aliphatic;-   R^(b) is H or optionally substituted C₁₋₆ aliphatic;-   each R^(c) is independently H or optionally substituted C₁₋₆    aliphatic;-   n is 1, 2, 3, 4, or 5;-   p is 0, 1, 2, 3, or 4; and-   r is 0, 1, or 2.

In certain embodiments, Ring A is an optionally substituted 5-memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, Ring A is anoptionally substituted 5-membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, Ring A is dihydrofuro[2,3-b]tetrahydrofuran,furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,isothiazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4thiadiazolyl, thiazolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, or 1,3,4-triazolyl; each of which is optionallysubstituted.

In certain embodiments, Ring A is imidazolidinyl, imidazolinyl,imidazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, or 1,3,4-triazolyl; each of which isoptionally substituted.

In certain embodiments, Ring A is pyrazolidinyl, pyrazolinyl, orpyrazolyl; each of which is optionally substituted.

In certain embodiments, Ring A is

In certain embodiments, Ring B is an optionally substituted 6-memberedaryl. In certain embodiments, Ring B is an optionally substituted6-membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, Ring B is phenyl, 2H,6H-1,5,2-dithiazinyl,pyrimidinyl, pyranyl, pyrazinyl, pyridazinyl, pyridinyl, pyridyl,pyrimidinyl, or triazinyl; each of which is optionally substituted.

In certain embodiments, Ring B is phenyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyridinyl, pyridyl, or pyrimidinyl; each of which isoptionally substituted.

In certain embodiments, Ring B is phenyl or pyridinyl.

In certain embodiments, Ring B is

In certain embodiments, Ring C is an optionally substituted 5-memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, Ring C is anoptionally substituted 5-membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, Ring C is dihydrofuro[2,3-b]tetrahydrofuran,furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,isothiazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4thiadiazolyl, thiazolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, or 1,3,4-triazolyl; each of which is optionallysubstituted.

In certain embodiments, Ring C is imidazolidinyl, imidazolinyl,imidazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, or 1,3,4-triazolyl; each of which isoptionally substituted.

In certain embodiments, Ring C is pyrazolidinyl, pyrazolinyl, orpyrazolyl; each of which is optionally substituted.

In certain embodiments, Ring C is

In certain embodiments, R^(a) is H.

In certain embodiments, R^(a) is optionally substituted C₁₋₆ aliphatic.In certain embodiments, R^(a) is methyl, ethyl, ethyl, propyl, i-propyl,butyl, s-butyl, t-butyl, straight or branched pentyl, or straight orbranched hexyl; each of which is optionally substituted.

In certain embodiments, R^(b) is H.

In certain embodiments, R^(b) is optionally substituted C₁₋₆ aliphatic.In certain embodiments, R^(b) is methyl, ethyl, ethyl, propyl, i-propyl,butyl, s-butyl, t-butyl, straight or branched pentyl, or straight orbranched hexyl; each of which is optionally substituted.

In certain embodiments, X is absent.

In certain embodiments, X is —CH═CH—, —O—, —S—, —SO₂—, —SO—, —C(O)—,—CO₂—, —C(O)N(R)—, —OC(O)N(R)—, —NRC(O)—, —NRC(O)N(R)—, —NRSO₂—, or—N(R)—.

In certain embodiments, X is —CH═CH—, —C≡C—, —O—, —S—, —SO₂—, —SO—,—C(O)—, —CO₂—, —C(O)N(H)—, —OC(O)N(H)—, —NHC(O)—, —NHC(O)N(H)—, —NHSO₂—,or —N(H)—.

In certain embodiments, X is —CH═CH—, —C≡C—, —O—, —S—, —SO₂—, —SO—,—C(O)—, —CO₂—, —C(O)N(Me)-, —OC(O)N(Me)-, —NMeC(O)—, —NMeC(O)N(Me)-,—NMeSO₂—, or —N(Me)-.

In certain embodiments, X is —CH═CH—, —C≡C—, —O—, —S—, —SO₂—, —SO—,—CO₂—, —OC(O)N(Me)-, or —N(Me)-.

In certain embodiments, Y is absent.

In certain embodiments, Y is a divalent C₃₋₁₀ aryl, a divalent 3-8membered saturated or partially unsaturated carbocyclic ring, a divalent3-7 membered heterocylic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or a divalent 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; each of which is optionallysubstituted.

In certain embodiments, Y is an optionally substituted divalent C₃₋₁₀aryl. In certain embodiments, Y is an optionally substituted divalent3-8 membered saturated or partially unsaturated carbocyclic ring. Incertain embodiments, Y is an optionally substituted divalent 3-7membered heterocylic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In certain embodiments, Y is anoptionally substituted divalent 5-6 membered monocyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

In certain embodiments, Y is an optionally substituted divalent phenyl,naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl,[4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl,tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl.

In certain embodiments, Y is an optionally substituted divalentpyrrolidine, piperidine, or morpholine.

In certain embodiments, Y is

In certain embodiments, n is 1, 2, 3, or 4.

In certain embodiments, p is 0, 1, or 2.

In certain embodiments, r is 0.

In certain embodiments, each of Ring A, Ring B, Ring C, X, Y, R, R^(a),R^(b), n, p, and r, is as defined above and described in embodiments,classes and subclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-a,

or a pharmaceutically acceptable salt thereof, wherein each of Ring B,Ring C, X, Y, R, R^(a), R^(b), n, and p, is as defined above anddescribed in embodiments, classes and subclasses above and herein,singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-b,

or a pharmaceutically acceptable salt thereof, wherein each of Ring C,X, Y, R, R^(a), R^(b), n, and p, is as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the present invention provides a compound offormula I-c,

or a pharmaceutically acceptable salt thereof, wherein each of Ring C,X, Y, R, R^(a), R^(b), n, and p, is as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the present invention provides a compound offormula I-d,

or a pharmaceutically acceptable salt thereof, wherein each of Ring B,Ring C, X, Y, R, R^(a), R^(b), n, p, and r, is as defined above anddescribed in embodiments, classes and subclasses above and herein,singly or in combination.

In certain embodiments, the invention provides a compound selected fromTable 1:

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

In some embodiments, the present invention provides a compound selectedfrom those depicted above, or a pharmaceutically acceptable saltthereof.

In certain embodiments, the compounds of the invention provide fordecreased cytotoxicity or low cytotoxicity in a PBMC cellular assay.

Various structural depictions may show a heteroatom without an attachedgroup, radical, charge, or counterion. Those of ordinary skill in theart are aware that such depictions are meant to indicate that theheteroatom is attached to hydrogen (e.g.,

is understood to be

In certain embodiments, the compounds of the invention were synthesizedin accordance with the schemes provided in the Examples below.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably inhibit IRAK, or a mutant thereof,in a biological sample or in a patient. In certain embodiments, theamount of compound in compositions of this invention is such that iseffective to measurably inhibit IRAK, or a mutant thereof, in abiological sample or in a patient. In certain embodiments, a compositionof this invention is formulated for administration to a patient in needof such composition.

The term “patient” or “subject”, as used herein, means an animal,preferably a mammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat are used in the compositions of this invention include, but are notlimited to, ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

Compositions of the present invention are administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention include aqueous or oleaginous suspension.These suspensions are formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that are employed are water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium.

For this purpose, any bland fixed oil employed includes synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents that arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms arealso be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention are orallyadministered in any orally acceptable dosage form. Exemplary oral dosageforms are capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents are optionally also added.

Alternatively, pharmaceutically acceptable compositions of thisinvention are administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention are alsoadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches are also used.

For topical applications, provided pharmaceutically acceptablecompositions are formulated in a suitable ointment containing the activecomponent suspended or dissolved in one or more carriers. Exemplarycarriers for topical administration of compounds of this are mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, provided pharmaceutically acceptable compositions can beformulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Pharmaceutically acceptable compositions of this invention areoptionally administered by nasal aerosol or inhalation. Suchcompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and are prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or otherconventional solubilizing or dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that are optionallycombined with the carrier materials to produce a composition in a singledosage form will vary depending upon the host treated, the particularmode of administration. Preferably, provided compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe compound can be administered to a patient receiving thesecompositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

The present invention furthermore relates to a method for treating asubject suffering from an IRAK related disorder, comprisingadministering to said subject an effective amount of a compound offormula I and related formulae.

The present invention preferably relates to a method, wherein the IRAKassociated disorder is an autoimmune disorder or condition associatedwith an overactive immune response or cancer. The present inventionfurthermore relates to a method of treating a subject suffering from animmunoregulatory abnomality, comprising administering to said subject acompound of formula (I), and related formulae in an amount that iseffective for treating said immunoregulatory abnormality.

The present invention preferably relates to a method wherein theimmunoregulatory abnormality is an autoimmune or chronic inflammatorydisease selected from the group consisting of: allergic diseases,amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus,chronic rheumatoid arthritis, type I diabetes mellitus, inflammatorybowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn'sdisease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,autoimmune myositis, Wegener's granulomatosis, ichthyosis, Gravesophthalmopathy and asthma.

The present invention furthermore relates to a method wherein theimmunoregulatory abnormality is bone marrow or organ transplantrejection or graft-versus-host disease.

The present invention furthermore relates to a method wherein theimmunoregulatory abnormality is selected from the group consisting of:transplantation of organs or tissue, graft-versus-host diseases broughtabout by transplantation, autoimmune syndromes including rheumatoidarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis,multiple sclerosis, systemic sclerosis, myasthenia gravis, type Idiabetes, uveitis, posterior uveitis, allergic encephalomyelitis,glomerulonephritis, post-infectious autoimmune diseases includingrheumatic fever and post-infectious glomerulonephritis, inflammatory andhyperproliferative skin diseases, psoriasis, atopic dermatitis, contactdermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichenplanus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupuserythematosus, acne, alopecia areata, keratoconjunctivitis, vernalconjunctivitis, uveitis associated with Behcet's disease, keratitis,herpetic keratitis, conical cornea, dystrophia epithelialis corneae,corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves'opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollenallergies, reversible obstructive airway disease, bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma,chronic or inveterate asthma, late asthma and airwayhyper-responsiveness, bronchitis, gastric ulcers, vascular damage causedby ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns, coeliac diseases, proctitis,eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerativecolitis, migraine, rhinitis, eczema, interstitial nephritis,Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy,multiple myositis, Guillain-Barre syndrome, Meniere's disease,polyneuritis, multiple neuritis, mononeuritis, radiculopathy,hyperthyroidism, Basedow's disease, pure red cell aplasia, aplasticanemia, hypoplastic anemia, idiopathic thrombocytopenic purpura,autoimmune hemolytic anemia, agranulocytosis, pernicious anemia,megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis,fibroid lung, idiopathic interstitial pneumonia, dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity,cutaneous T cell lymphoma, chronic lymphocytic leukemia,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenesis, metastasis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis, sclerosing cholangitis, partial liver resection,acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock,or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis,alcoholic cirrhosis, hepatic failure, fulminant hepatic failure,late-onset hepatic failure, “acute-on-chronic” liver failure,augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMVinfection, AIDS, cancer, senile dementia, parkison diseases, trauma, andchronic bacterial infection.

In certain embodiments, disorders associated with IRAK are selected fromRheumatoid Arthritis, Psoriatic arthritis, Osteoarthritis, SystemicLupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis,Osteoporosis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type Idiabetes, Type II diabetes, Inflammatory Bowel Disease (Crohn's Diseaseand Ulcerative Colitis), Hyperimmunoglobulinemia D and periodic feversyndrome, Cryopyrin-associated periodic syndromes, Schnitzler'ssyndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still'sdisease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis,Stroke, Atherosclerosis, Celiac disease, DIRA (Deficiency of IL-1Receptor Antagonist), Alzheimer's disease, Parkinson's disease, andCancer.

In certain embodiments, the cancer is selected from carcinoma, lymphoma,blastoma (including medulloblastoma and retinoblastoma), sarcoma(including liposarcoma and synovial cell sarcoma), neuroendocrine tumors(including carcinoid tumors, gastrinoma, and islet cell cancer),mesothelioma, schwannoma (including acoustic neuroma), meningioma,adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include squamous cell cancer (e.g.,epithelial squamous cell cancer), lung cancer including small-cell lungcancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of thelung and squamous carcinoma of the lung, cancer of the peritoneum,hepatocellular cancer, gastric or stomach cancer includinggastrointestinal cancer, pancreatic cancer, glioblastoma, cervicalcancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breastcancer (including metastatic breast cancer), colon cancer, rectalcancer, colorectal cancer, endometrial or uterine carcinoma, salivarygland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer,thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma,testicular cancer, esophageal cancer, tumors of the biliary tract, aswell as head and neck cancer.

In certain embodiments, the cancer is brain, lung, colon, epidermoid,squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal,kidney, liver, ovarian, prostate, colorectal, uterine, rectal,oesophageal, testicular, gynecological, thyroid cancer, melanoma,hematologic malignancies such as acute myelogenous leukemia, multiplemyeloma, chronic myelogenous leukemia, myeloid cell leukemia, glioma,Kaposi's sarcoma, or any other type of solid or liquid tumors. In someembodiments, the cancer is metastatic cancer. In some embodiments, thecancer is colorectal cancer. In some embodiments, the cancer is coloncancer.

In various embodiments, compounds of formula (I), and related formulaeexhibit a IC50 for the binding to IRAK of less than about 5 μM,preferably less than about 1 μM and even more preferably less than about0.100 μM.

The method of the invention can be performed either in-vitro or in-vivo.The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be particularly determined by in-vitrotests, whether in the course of research or clinical application.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to inhibit IRAK activity, usuallybetween about one hour and one week. In-vitro treatment can be carriedout using cultivated cells from a biopsy sample or cell line.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models and models of transgenic animals. For thedetermination of certain stages in the signal transduction cascade,interacting compounds can be utilized in order to modulate the signal.The compounds according to the invention can also be used as reagentsfor testing IRAK-dependent signal transduction pathways in animalsand/or cell culture models or in the clinical diseases mentioned in thisapplication.

Moreover, the subsequent teaching of the present specificationconcerning the use of the compounds according to formula (I) and itsderivatives for the production of a medicament for the prophylactic ortherapeutic treatment and/or monitoring is considered as valid andapplicable without restrictions to the use of the compound for theinhibition of IRAK activity if expedient.

The invention also relates to the use of compounds according to formula(I) and/or physiologically acceptable salts thereof for the prophylacticor therapeutic treatment and/or monitoring of diseases that are caused,mediated and/or propagated by IRAK activity. Furthermore, the inventionrelates to the use of compounds according to formula (I) and/orphysiologically acceptable salts thereof for the production of amedicament for the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byIRAK activity. In certain embodiments, the invention provides the use ofa compound according to formula I or physiologically acceptable saltsthereof, for the production of a medicament for the prophylactic ortherapeutic treatment of a IRAK-mediated disorder.

Compounds of formula (I) and/or a physiologically acceptable saltthereof can furthermore be employed as intermediate for the preparationof further medicament active ingredients. The medicament is preferablyprepared in a non-chemical manner, e.g. by combining the activeingredient with at least one solid, fluid and/or semi-fluid carrier orexcipient, and optionally in conjunction with a single or more otheractive substances in an appropriate dosage form.

The compounds of formula (I) according to the invention can beadministered before or following an onset of disease once or severaltimes acting as therapy. The aforementioned compounds and medicalproducts of the inventive use are particularly used for the therapeutictreatment. A therapeutically relevant effect relieves to some extent oneor more symptoms of a disorder, or returns to normality, eitherpartially or completely, one or more physiological or biochemicalparameters associated with or causative of a disease or pathologicalcondition. Monitoring is considered as a kind of treatment provided thatthe compounds are administered in distinct intervals, e.g. in order toboost the response and eradicate the pathogens and/or symptoms of thedisease completely. Either the identical compound or different compoundscan be applied. The methods of the invention can also be used to reducethe likelihood of developing a disorder or even prevent the initiationof disorders associated with IRAK activity in advance or to treat thearising and continuing symptoms.

In the meaning of the invention, prophylactic treatment is advisable ifthe subject possesses any preconditions for the aforementionedphysiological or pathological conditions, such as a familialdisposition, a genetic defect, or a previously incurred disease.

The invention furthermore relates to a medicament comprising at leastone compound according to the invention and/or pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios. In certain embodiments, the inventionrelates to a medicament comprising at least one compound according tothe invention and/or physiologically acceptable salts thereof.

A “medicament” in the meaning of the invention is any agent in the fieldof medicine, which comprises one or more compounds of formula (I) orpreparations thereof (e.g. a pharmaceutical composition orpharmaceutical formulation) and can be used in prophylaxis, therapy,follow-up or aftercare of patients who suffer from diseases, which areassociated with IRAK activity, in such a way that a pathogenicmodification of their overall condition or of the condition ofparticular regions of the organism could establish at least temporarily.

In various embodiments, the active ingredient may be administered aloneor in combination with other treatments. A synergistic effect may beachieved by using more than one compound in the pharmaceuticalcomposition, i.e. the compound of formula (I) is combined with at leastanother agent as active ingredient, which is either another compound offormula (I) or a compound of different structural scaffold. The activeingredients can be used either simultaneously or sequentially.

Included herein are methods of treatment in which at least one chemicalentity provided herein is administered in combination with ananti-inflammatory agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor (TNF) antagonists, immunosuppressants and methotrexate.

Examples of NSAIDs include, but are not limited to, ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors such as celecoxib, valdecoxib, lumiracoxib and/or etoricoxib.

In some embodiments, the anti-inflammatory agent is a salicylate.Salicylates include by are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be cortisone, dexamethasone, methylprednisolone,prednisolone, prednisolone sodium phosphate, or prednisone.

In additional embodiments the anti-inflammatory agent is a gold compoundsuch as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which atleast one anti-inflammatory compound is an anti-monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, or infliximab, which is an anti-TNF alpha monoclonalantibody.

Still other embodiments of the invention pertain to combinations inwhich at least one active agent is an immunosuppressant compound such asan immunosuppressant compound chosen from methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined above may be applied as a monotherapyor may involve, in addition to the herein disclosed compounds of formulaI, conventional surgery or radiotherapy or medicinal therapy. Suchmedicinal therapy, e.g. a chemotherapy or a targeted therapy, mayinclude one or more, but preferably one, of the following anti-tumoragents:

Alkylating agents: such as altretamine, bendamustine, busulfan,carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine,ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol,mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan,mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide,palifosfamide, pipobroman, trofosfamide, uramustine, TH-302⁴, VAL-083⁴;Platinum Compounds: such as carboplatin, cisplatin, eptaplatin,miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin,satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;DNA altering agents: such as amrubicin, bisantrene, decitabine,mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine,brostallicin, pixantrone, laromustine^(1,3);Topoisomerase Inhibitors: such as etoposide, irinotecan, razoxane,sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptiniumacetate, voreloxin;Microtubule modifiers: such as cabazitaxel, docetaxel, eribulin,ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine,vindesine, vinflunine; fosbretabulin, tesetaxel;Antimetabolites: such as asparaginase³, azacitidine, calciumlevofolinate, capecitabine, cladribine, cytarabine, enocitabine,floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine,methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine,thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed,sapacitabine, tegafur^(2,3), trimetrexate;Anticancer antibiotics: such as bleomycin, dactinomycin, doxorubicin,epirubicin, idarubicin, levamisole, miltefosine, mitomycin C,romidepsin, streptozocin, valrubicin, zinostatin, zorubicin,daunurobicin, plicamycin; aclarubicin, peplomycin, pirarubicin;Hormones/Antagonists: such as abarelix, abiraterone, bicalutamide,buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone,estradiol, fluocortolone fluoxymesterone, flutamide, fulvestrant,goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin,nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen,thyrotropin alfa, toremifene, trilostane, triptorelin,diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol,orteronel, enzalutamide^(1,3);Aromatase inhibitors: such as aminoglutethimide, anastrozole,exemestane, fadrozole, letrozole, testolactone; formestane;Small molecule kinase inhibitors: such as crizotinib, dasatinib,erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib,ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib,gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib,dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib,linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib,perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib,tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib,apatinib⁴, cabozantinib S-malate^(1,3), ibrutinib^(1,3), icotinib⁴,buparlisib², cipatinib⁴, cobimetinib^(1,3), idelalisib^(1,3),fedratinib¹, XL-647⁴;Photosensitizers: such as methoxsalen³; porfimer sodium, talaporfin,temoporfin;Antibodies: such as alemtuzumab, besilesomab, brentuximab vedotin,cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab,tositumomab, trastuzumab, bevacizumab, pertuzumab^(2,3); catumaxomab,elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab,nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab,rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab,matuzumab, dalotuzumab^(1,2,3), onartuzumab^(1,3), racotumomab¹,tabalumab^(1,3), EMD-525797⁴, nivolumab^(1,3);Cytokines: such as aldesleukin, interferon alfa², interferon alfa2a³,interferon alfa2b^(2,3); celmoleukin, tasonermin, teceleukin,oprelvekin^(1,3), recombinant interferon beta-1a⁴;Drug Conjugates: such as denileukin diftitox, ibritumomab tiuxetan,iobenguane I123, prednimustine, trastuzumab emtansine, estramustine,gemtuzumab, ozogamicin, aflibercept; cintredekin besudotox, edotreotide,inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox,technetium (99mTc) arcitumomab^(1,3), vintafolide^(1,3);Vaccines: such as sipuleucel³; vitespen³, emepepimut-S³, oncoVAX⁴,rindopepimut³, troVax⁴, MGN-1601⁴, MGN-1703⁴; andMiscellaneous: alitretinoin, bexarotene, bortezomib, everolimus,ibandronic acid, imiquimod, lenalidomide, lentinan, metirosine,mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel³,sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin,vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide,entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib,lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin,pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat,thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar,gendicine⁴, picibanil⁴, reolysin⁴, retaspimycin hydrochloride^(1,3),trebananib^(2,3), virulizin⁴, carfilzomib^(1,3), endostatin⁴,immucothel⁴, belinostat³, MGN-1703⁴. (¹Prop. INN (Proposed InternationalNonproprietary Name); ²Rec. INN (Recommended InternationalNonproprietary Names); ³USAN (United States Adopted Name); ⁴no INN).

In another aspect, the invention provides for a kit consisting ofseparate packs of an effective amount of a compound according to theinvention and/or pharmaceutically acceptable salts, derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally, an effective amount of a further activeingredient. The kit comprises suitable containers, such as boxes,individual bottles, bags or ampoules. The kit may, for example, compriseseparate ampoules, each containing an effective amount of a compoundaccording to the invention and/or pharmaceutically acceptable salts,derivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and an effective amount of a further activeingredient in dissolved or lyophilized form.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment is administered afterone or more symptoms have developed. In other embodiments, treatment isadministered in the absence of symptoms. For example, treatment isadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment is also continued aftersymptoms have resolved, for example to prevent or delay theirrecurrence.

The compounds and compositions, according to the method of the presentinvention, are administered using any amount and any route ofadministration effective for treating or lessening the severity of adisorder provided above. The exact amount required will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. Compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention are administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 100mg/kg and preferably from about 1 mg/kg to about 50 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

In certain embodiments, a therapeutically effective amount of a compoundof the formula (I), and related formulae and of the other activeingredient depends on a number of factors, including, for example, theage and weight of the animal, the precise disease condition whichrequires treatment, and its severity, the nature of the formulation andthe method of administration, and is ultimately determined by thetreating doctor or vet. However, an effective amount of a compound isgenerally in the range from 0.1 to 100 mg/kg of body weight of therecipient (mammal) per day and particularly typically in the range from1 to 10 mg/kg of body weight per day. Thus, the actual amount per dayfor an adult mammal weighing 70 kg is usually between 70 and 700 mg,where this amount can be administered as an individual dose per day orusually in a series of part-doses (such as, for example, two, three,four, five or six) per day, so that the total daily dose is the same. Aneffective amount of a salt or solvate or of a physiologically functionalderivative thereof can be determined as the fraction of the effectiveamount of the compound per se.

In certain embodiments, the pharmaceutical formulations can beadministered in the form of dosage units, which comprise a predeterminedamount of active ingredient per dosage unit. Such a unit can comprise,for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularlypreferably 5 mg to 100 mg, of a compound according to the invention,depending on the disease condition treated, the method of administrationand the age, weight and condition of the patient, or pharmaceuticalformulations can be administered in the form of dosage units whichcomprise a predetermined amount of active ingredient per dosage unit.Preferred dosage unit formulations are those which comprise a daily doseor part-dose, as indicated above, or a corresponding fraction thereof ofan active ingredient. Furthermore, pharmaceutical formulations of thistype can be prepared using a process, which is generally known in thepharmaceutical art.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms optionally contain inert diluents commonly usedin the art such as, for example, water or other solvents, solubilizingagents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions are formulated according to the known art usingsuitable dispersing or wetting agents and suspending agents. The sterileinjectable preparation are also a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This is accomplished by the useof a liquid suspension of crystalline or amorphous material with poorwater solubility. The rate of absorption of the compound then dependsupon its rate of dissolution that, in turn, may depend upon crystal sizeand crystalline form. Alternatively, delayed absorption of aparenterally administered compound form is accomplished by dissolving orsuspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-glycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form also optionally comprises buffering agents.

Solid compositions of a similar type are also employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype are also employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms optionally also comprisebuffering agents. They optionally contain opacifying agents and can alsobe of a composition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as required. Ophthalmicformulation, ear drops, and eye drops are also contemplated as beingwithin the scope of this invention. Additionally, the present inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms can be made by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting IRAK activity in a biological sample comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting IRAK, or a mutant thereof, activity in a biological sample ina positive manner, comprising the step of contacting said biologicalsample with a compound of this invention, or a composition comprisingsaid compound.

The compounds of the invention are useful in-vitro as unique tools forunderstanding the biological role of IRAK, including the evaluation ofthe many factors thought to influence, and be influenced by, theproduction of IRAK and the interaction of IRAK. The present compoundsare also useful in the development of other compounds that interact withIRAK since the present compounds provide important structure-activityrelationship (SAR) information that facilitate that development.Compounds of the present invention that bind to IRAK can be used asreagents for detecting IRAK in living cells, fixed cells, in biologicalfluids, in tissue homogenates, in purified, natural biologicalmaterials, etc. For example, by labeling such compounds, one canidentify cells expressing IRAK. In addition, based on their ability tobind IRAK, compounds of the present invention can be used in in-situstaining, FACS (fluorescence-activated cell sorting), sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE), ELISA(enzyme-linked immunoadsorptive assay), etc., enzyme purification, or inpurifying cells expressing IRAK inside permeabilized cells. Thecompounds of the invention can also be utilized as commercial researchreagents for various medical research and diagnostic uses. Such uses caninclude but are not limited to: use as a calibration standard forquantifying the activities of candidate IRAK inhibitors in a variety offunctional assays; use as blocking reagents in random compoundscreening, i.e. in looking for new families of IRAK ligands, thecompounds can be used to block recovery of the presently claimed IRAKcompounds; use in the co-crystallization with IRAK enzyme, i.e. thecompounds of the present invention will allow formation of crystals ofthe compound bound to IRAK, enabling the determination ofenzyme/compound structure by x-ray crystallography; other research anddiagnostic applications, wherein IRAK is preferably activated or suchactivation is conveniently calibrated against a known quantity of anIRAK inhibitor, etc.; use in assays as probes for determining theexpression of IRAK in cells; and developing assays for detectingcompounds which bind to the same site as the IRAK binding ligands.

The compounds of the invention can be applied either themselves and/orin combination with physical measurements for diagnostics of treatmenteffectiveness. Pharmaceutical compositions containing said compounds andthe use of said compounds to treat IRAK-mediated conditions is apromising, novel approach for a broad spectrum of therapies causing adirect and immediate improvement in the state of health, whether inhuman or in animal. The orally bioavailable and active new chemicalentities of the invention improve convenience for patients andcompliance for physicians.

The compounds of formula (I), their salts, isomers, tautomers,enantiomeric forms, diastereomers, racemates, derivatives, prodrugsand/or metabolites are characterized by a high specificity andstability, low manufacturing costs and convenient handling. Thesefeatures form the basis for a reproducible action, wherein the lack ofcross-reactivity is included, and for a reliable and safe interactionwith the target structure.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Modulation of IRAK, or a mutant thereof, activity in a biological sampleis useful for a variety of purposes that are known to one of skill inthe art. Examples of such purposes include, but are not limited to,blood transfusion, organ transplantation, biological specimen storage,and biological assays.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

The symbols and conventions used in the following descriptions ofprocesses, schemes, and examples are consistent with those used in thecontemporary scientific literature, for example, the Journal of theAmerican Chemical Society or the Journal of Biological Chemistry.

Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade).

All reactions were conducted at room temperature unless otherwise noted.All compounds of the present invention were synthesized by processesdeveloped by the inventors.

¹H NMR was recorded on a Bruker 400 MHz spectrometer, using residualsignal of deuterated solvent as internal reference. Chemical shifts (δ)are reported in ppm relative to the residual solvent signal (δ=2.49 ppmfor 1H NMR in DMSO-d6). ¹H NMR data are reported as follows: chemicalshift (multiplicity, coupling constants, and number of hydrogens).Multiplicity is abbreviated as follows: s (singlet), d (doublet), t(triplet), q (quartet), m (multiplet), br (broad).

LCMS-Analysis was performed under the following conditions:

-   Method: A: 0.1% TFA in H₂O, B: 0.1% TFA in ACN:-   Runtime: 6.5 min-   Flow Rate: 1.0 mL/min-   Gradient: 5-95% B in 4.5 min, wavelength 254 and 215 nM.-   Column: Waters Sunfire C18, 3.0×50 mm, 3.5 um, +ve mode-   Mass Scan: 100-900 Da

Compound numbers utilized in the Examples below correspond to compoundnumbers set forth supra.

The following abbreviations refer to the abbreviations used below:

Ac (acetyl), BINAP (2,2′-bis(disphenylphosphino)-1,1′-binaphthalene),dba (dibenzylidene acetone), Bu (Butyl), tBu (tert-Butyl), DCE(dichloroethane), DCM (Dichloromethane), δ (chemical shift), DIEPA(di-isopropyl ethylamine), DMA (dimethyl acetamide), DMSO (DimethylSulfoxide), DMF (N,N-Dimethylformamide), Dppf (1,1′-bis(diphenylphosphine ferrocene)), EA (Ethyl acetate), EtOH (Ethanol), eq(equivalent), g (gram), cHex (Cyclohexane), HATU(N-[(Dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminiumhexafluorophosphate), HPLC (High Performance Liquid Chromatography), h/hr (hour),LDA (lithium diisopropyl amine), LiHMDS (lithiumbis(trimethylsilyl)amide), MHz (Megahertz), MeOH (Methanol), min(minute), mL/ml (milliliter), mmol (millimole), mM (millimolar), mp(melting point), MS (Mass Spectrometry), MW (microwave), NMR (NuclearMagnetic Resonance), O/N (overnight), PBS (Phosphate Buffered Saline),SNAP (silica gel column), RT (room temperature), TEA (Triethyl amine),TFA (Trifluoroacetic acid), THF (Tetrahydrofuran), TLC (Thin LayerChromatography).

In general, the compounds according to Formula (I) and related formulaeof this invention can be prepared from readily available startingmaterials. If such starting materials are not commercially available,they may be prepared by standard synthetic techniques. In general, thesynthesis pathways for any individual compound of Formula (I) andrelated formulae will depend on the specific substituents of eachmolecule, such factors being appreciated by those of ordinary skilled inthe art. The following general methods and procedures describedhereinafter in the examples may be employed to prepare compounds ofFormula (I) and related formulae. Reaction conditions depicted in thefollowing schemes, such as temperatures, solvents, or co-reagents, aregiven as examples only and are not restrictive. It will be appreciatedthat where typical or preferred experimental conditions (i.e. reactiontemperatures, time, moles of reagents, solvents etc.) are given, otherexperimental conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvents used, but such conditions can be determined by the personskilled in the art, using routine optimisation procedures. For all theprotection and deprotection methods, see Philip J. Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and,Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in OrganicSynthesis”, Wiley Interscience, 3^(rd) Edition 1999.

¹H NMR was recorded on a Bruker 400 MHz spectrometer, using residualsignal of deuterated solvent as internal reference. Chemical shifts (δ)are reported in ppm relative to the residual solvent signal (δ=2.49 ppmfor 1H NMR in DMSO-d6). 1H NMR data are reported as follows: chemicalshift (multiplicity, coupling constants, and number of hydrogens).Multiplicity is abbreviated as follows: s (singlet), d (doublet), t(triplet), q (quartet), m (multiplet), br (broad).

LCMS-Analysis was performed under the following conditions:

-   Method: A: 0.1% TFA in H₂O, B: 0.1% TFA in ACN:-   Runtime: 6.5 min-   Flow Rate: 1.0 mL/min-   Gradient: 5-95% B in 4.5 min, wavelength 254 and 215 nM.-   Column: Waters Sunfire C18, 3.0×50 mm, 3.5 um, +ve mode-   Mass Scan: 100-900 Da

Intermediates:

6-(1-tert-Butoxycarbonyl-1H-pyrazol-4-yl)-pyridine-2-carboxylic acidmethyl ester (1b)

A mixture of 6-Bromo-pyridine-2-carboxylic acid methyl ester (4940 mg;22.87 mmol; 1.00 eq.),4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylicacid tert-butyl ester (7399 mg; 25.15 mmol; 1.10 eq.), potassiumcarbonate (3476 mg; 25.15 mmol; 1.10 eq.) in dioxane (130 mL) and water(13 mL) was degassed, then to it was added palladiumtritert-butylphosphane (584 mg; 1.14 mmol; 0.05 eq.), and the mixturewas stirred at 40° C. for 24 hr. LC-MS showed the clean desiredcompound. The reaction solution was diluted with EA (100 mL), washedwith brine (100 mL×2), dried, evaporated, and the resulting residue wastreated with ether. The solid precipitated out, was filtered to provide5500 mg of the title compound as a white solid. Yield 79%. LC-MS (M+1):304.

6-(1H-Pyrazol-4-yl)-pyridine-2-carboxylic acid methyl ester (1c)

To a solution of6-(1-tert-Butoxycarbonyl-1H-pyrazol-4-yl)-pyridine-2-carboxylic acidmethyl ester (5500 mg; 18.13 mmol; 1.00 eq.) in methanol (30 mL) wasadded 4.0M HCl in dioxane hydrogen chloride (36266 mL; 145.06 mmol; 8.00eq.) at 0° C., and the mixture was stirred at RT for 3 hr. LC-MS showedthe reaction was completed. The reaction solution was diluted with EA(30 mL), filtered, and the collected solid was dissolved water (50 mL).Disodium carbonate (5765 mg; 54.40 mmol; 3.00 eq.) was added, stirredfor 1 hr at RT, filtered, and collected to provide the title compound asa white solid (2500 mg). Yield 68%. LC-MS (M+1): 204.

6-[1-(6-Amino-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid methylester (1d)

A mixture of 6-(1H-Pyrazol-4-yl)-pyridine-2-carboxylic acid methyl ester(1000 mg; 4.92 mmol; 1.00 eq.), methanesulfonic acid6-tert-butoxycarbonylamino-hexyl ester (1599 mg; 5.41 mmol; 1.10 eq.)and Cs₂CO₃ (1763 mg; 5.41 mmol; 1.10 eq.) in DMF (10 mL) was stirred at80° C. for 3 hr. LC-MS showed the desired compound. The reaction wascooled, diluted with water (50 mL), extracted with DCM (100 mL×2), andthe organic layer was washed with brine and dried, providing the residueas6-[1-(6-tert-Butoxycarbonylamino-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylicacid methyl ester. To the above product was added methanol (6 mL), and4.0M hydrogen chloride in dioxane (6.15 mL; 24.61 mmol; 5.00 eq.), andstirred at RT for overnight. The solvent was removed and the residue wasdissolved in water (10 mL), washed with EA (10 mL×2). The organic layerwas discarded, and to the aqueous layer was added disodium carbonate(1304 mg; 12.30 mmol; 2.50 eq.). The mixture was extracted with DCM (100mL×2), the organic layers were combined, washed with Brine (20 mL),dried over MgSO₄ and the solvent was evaporated affording 1310 mg of thetitle compound as a white off solid. Yield 88%. LC-MS (M+1): 303.

6-[1-(6-{[1-(1-tert-Butoxycarbonyl-piperidin-4-yl)-4-nitro-1H-pyrazole-3-carbonyl]-amino}-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylicacid methyl ester (1e)

A mixture of 4-(3-Carboxy-4-nitro-pyrazol-1-yl)-piperidine-1-carboxylicacid tert-butyl ester lithium (490.00 mg; 1.42 mmol; 1.00 eq.), HATU(1317 mg, 3.47 mmol, 1.2 eq) and Ethyl-diisopropyl-amine (0.31 mL; 1.77mmol; 1.25 eq.) in DMF (10 mL) were stirred at RT for 10 min.6-[1-(6-Amino-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid methylester (385.10 mg; 1.27 mmol; 0.90 eq.) was added and the mixture wasstirred for 2 hr at RT. The solvent was removed, water was added (40mL), extracted with DCM (100×2), and the organic layer was washed withaqueous 5% NaHCO₃, then brine. The solvent was removed and the crudeproduct was purified by SNAP column (100 G eluented with 20-100% EA inhexane), providing the title compound (210 mg, yield 23%). LC-MS (M+1):625.

6-[1-(6-{[4-Amino-1-(1-tert-butoxycarbonyl-piperidin-4-yl)-1H-pyrazole-3-carbonyl]-amino}-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylicacid methyl ester (1f)

To a solution of6-[1-(6-{[1-(1-tert-Butoxycarbonyl-piperidin-4-yl)-4-nitro-1H-pyrazole-3-carbonyl]-amino}-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylicacid methyl ester (450.00 mg; 0.72 mmol; 1.00 eq.) in 40 mL methanol wasadded 10% Pd/C 280 mg (wet). The mixture was put on a par shaker at 50psi for 2 hr at RT, the catalyst was filtered off, and the solvent wasremoved, providing a residue as the title compound, which was directlyused for the next step reaction. LC-MS (M+1): 595.

Lithium6-[1-(6-{[4-Amino-1-(1-tert-butoxycarbonyl-piperidin-4-yl)-1H-pyrazole-3-carbonyl]-amino}-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylate(1g)

A mixture of Lithium6-[1-(6-{[4-Amino-1-(1-tert-butoxycarbonyl-piperidin-4-yl)-1H-pyrazole-3-carbonyl]-amino}-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylate(428 mg; 0.72 mmol; 1.00 eq.), lithium hydroxide hydrate (60 mg; 1.44mmol; 2.00 eq.) in THF (2 mL) and water (2 mL) was stirred at RT for 20min. LC-MS indicated the reaction was completed. The solvent was removedand the residue was directly used for the next step reaction. LC-MS(M+1): 580.

Example 1: tert-butyl4-{13,20-dioxo-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹ ⁴ ,¹⁸]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaen-16-yl}piperidine-1-carboxylate(26)

A mixture of lithium6-[1-(6-{[4-Amino-1-(1-tert-butoxycarbonyl-piperidin-4-yl)-1H-pyrazole-3-carbonyl]-amino}-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylate(422 mg; 0.72 mmol; 1.00 eq.), Ethyl-diisopropyl-amine (0.27 mL; 1.51mmol; 2.10 eq.) in DCM (50 mL) was added to3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (219 mg;0.86 mmol; 1.20 eq.), and stirred at RT for 4 days. DIEPA (0.05 mL) and3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (50 mg) wereadded, and the reaction was stirred for another 17 hr until reaction wascompleted by LC-MS. DCM (20 mL) was added, and water (20 mL) was added.The reaction was extracted and the organic layer was evaporated offsolvent, afforted residue (10 mg) was purified, providing compound 1.LC-MS (M+1): 563.

¹H NMR (400 MHz, Methanol-d4) δ 9.22 (d, J=0.7 Hz, 1H), 8.31 (s, 1H),8.01 (d, J=0.6 Hz, 1H), 7.96 (d, J=7.7 Hz, 1H), 7.89 (dd, J=7.7, 1.0 Hz,1H), 7.80 (dd, J=7.8, 1.0 Hz, 1H), 4.57-4.44 (m, 1H), 4.38-4.17 (m, 4H),3.52-3.35 (m, 2H), 3.02 (s, 2H), 2.29-1.91 (m, 6H), 1.89-1.70 (m, 4H),1.63 (q, J=6.5 Hz, 2H), 1.51 (s, 9H).

Example 216-(piperidin-4-yl)-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (16)

The compound from example 1 (0.72 mmol) was dissolved in methanol (2mL), and to it was added hydrogen chloride (1.80 mL; 7.20 mmol; 10.00eq.). The reaction was stirred at RT for 3 hr until completed. Thesolvent was removed and the residue was dissolved in DMSO, which wasthen purified by prep HPLC, affording the desired compound (80 mg, yield24%). LC-MS (M+1): 463.

Example 36-(1-methanesulfonylpiperidin-4-yl)-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (17)

A solution of16-(piperidin-4-yl)-4,5,12,15,16,19,25-Heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione(example 2, 8.00 mg; 0.02 mmol; 1.00 eq.) was dissolved in THF (0.5 mL)and to it were added Ethyl-diisopropyl-amine (0.01 mL; 0.04 mmol; 2.50eq.) and Methanesulfonyl chloride (2.58 mg; 0.02 mmol; 1.30 eq.). Themixture was stirred at RT for 30 min until complete as indicated byLC-MS. The solvent was evaporated and the residue purified by HPLC(20-60% acetonitrile and water contained 0.1% ammonia), providing 5 mgof a white solid. LC-MS (M+1): 541

¹H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 9.13 (s, 1H), 8.70-8.62 (m,1H), 8.38 (s, 1H), 8.12-7.98 (m, 2H), 7.89 (d, J=7.9 Hz, 1H), 7.80 (dd,J=20.8, 7.8 Hz, 1H), 4.47 (t, J=11.2 Hz, 1H), 4.21 (t, J=7.2 Hz, 2H),3.72 (d, J=11.9 Hz, 2H), 3.10 (m, 2H), 2.95 (s, 3H), 2.14 (m, 6H),1.75-1.63 (m, 4H), 1.50 (t, J=7.2 Hz, 2H), 1.26 (s, 2H).

Example 416-[1-(2,2-difluorocyclopropanecarbonyl)piperidin-4-yl]-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (18)

To a solution of 2,2-Difluoro-cyclopropanecarboxylic acid (8.97 mg; 0.07mmol; 2.00 eq.) in DMF (0.5 mL) was added HATU (17.47 mg; 0.05 mmol;1.25 eq.), and stirred at RT for 10 min. Ethyl-diisopropyl-amine (0.01mL; 0.06 mmol; 1.50 eq.) and16-(piperidin-4-yl)-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione(example 2, 17 mg; 0.04 mmol; 1.00 eq.) were added, and the mixture wasstirred for another 1 hr. LC-MS indicated the reaction was completed,and the product was purified by prep HPLC (9 mg, yield 50%). LC-MS(M+1): 567.

¹H NMR (400 MHz, DMSO-d6) δ 12.83-12.65 (m, 1H), 9.13 (s, 1H), 8.65 (dt,J=13.2, 6.3 Hz, 1H), 8.41-8.28 (m, 1H), 8.13-7.95 (m, 2H), 7.95-7.71 (m,2H), 4.63 (s, 1H), 4.48 (d, J=13.4 Hz, 1H), 4.21 (t, J=7.5 Hz, 3H),3.25-3.5 (m, 4H), 2.91 (q, J=12.7 Hz, 1H), 2.13 (d, J=9.7 Hz, 3H),2.01-1.75 (m, 4H), 1.68 (s, 4H), 1.55-1.41 (m, 2H).

Example 5N-cyclopropyl-4-{13,20-dioxo-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaen-16-yl}piperidine-1-carboxamide(19)

A mixture of16-(piperidin-4-yl)-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione(example 2, 17 mg; 0.04 mmol; 1.00 eq.), Ethyl-diisopropyl-amine (0.01mL; 0.06 mmol; 1.50 eq.) and Isocyanato-cyclopropane (6 mg; 0.07 mmol;2.00 eq.) in DMF (0.5 mL) was stirred at RT for 1 hr. After completion(by LC-MS), the reaction was purified by prep HPLC, providing 11 mg(white solid) of the title compound (yield 54%). LC-MS (M+1): 546.

¹H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 9.13 (s, 1H), 8.63 (d, J=6.2Hz, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 8.02 (t, J=7.7 Hz, 1H), 7.92-7.75(m, 2H), 6.64 (s, 1H), 4.48 (t, J=11.5 Hz, 1H), 4.21 (t, J=7.2 Hz, 2H),4.14-3.97 (m, 3H), 2.82 (t, J=12.6 Hz, 2H), 2.22-2.01 (m, 4H), 1.98 (s,1H), 1.91-1.76 (m, 2H), 1.69 (q, J=7.5 Hz, 4H), 1.56-1.37 (m, 2H),0.68-0.45 (m, 2H), 0.40 (d, J=3.2 Hz, 2H).

Example 66-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (23)

A mixture of16-(piperidin-4-yl)-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione(example 2, 11.00 mg; 0.02 mmol; 1.00 eq.), Ethyl-diisopropyl-amine(0.02 mL; 0.10 mmol; 4.00 eq.), (2-Chloro-ethyl)-dimethyl-aminehydrochloride (2) (8.59 mg; 0.05 mmol; 2.00 eq.), and potassium iodidein DMF (0.5 mL) was stirred at 100° C. for 24 hr. The mixture waspurified by prep HPLC, providing the title compound as a white solid (3mg). LC-MS (M+1): 534.

¹H NMR (400 MHz, Methanol-d4) δ 9.23 (s, 1H), 8.30 (d, J=1.6 Hz, 1H),8.07-7.92 (m, 2H), 7.81 (d, J=7.7 Hz, 1H), 4.28 (t, J=7.3 Hz, 3H), 3.44(t, J=7.7 Hz, 3H), 3.13 (d, J=12.4 Hz, 3H), 2.61 (s, 4H), 2.40-2.08 (m,14H), 1.81 (q, J=7.6 Hz, 5H), 1.65 (q, J=7.0 Hz, 2H).

Example 716-[1-(2-hydroxyethyl)piperidin-4-yl]-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (22)

A mixture of16-(piperidin-4-yl)-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione(example 2, 8.00 mg; 0.02 mmol; 1.00 eq.), Ethyl-diisopropyl-amine (0.01mL; 0.04 mmol; 2.20 eq.), and 2-Bromo-ethanol (2.81 mg; 0.02 mmol; 1.30eq.) in DMF (0.5 mL) was stirred at RT for 1 hr, then 60° C. for another5 hr. The reaction was purified by prep HPLC, providing the titlecompound as a white solid (5 mg). LC-MS (M+1): 507.

¹H NMR (500 MHz, Methanol-d4) δ 9.19 (d, J=1.8 Hz, 1H), 8.27 (d, J=2.2Hz, 1H), 8.06-7.89 (m, 2H), 7.86 (dd, J=7.8, 2.3 Hz, 1H), 7.77 (dd,J=7.8, 2.3 Hz, 1H), 4.58 (s, 1H), 4.34-4.18 (m, 3H), 3.74 (t, J=6.1 Hz,2H), 3.40 (t, J=7.6 Hz, 2H), 3.18 (d, J=11.4 Hz, 2H), 2.67 (d, J=5.8 Hz,2H), 2.38 (t, J=11.8 Hz, 2H), 2.18 (td, J=15.0, 14.5, 9.8 Hz, 6H), 1.79(p, J=7.4 Hz, 4H), 1.62 (q, J=6.8 Hz, 2H).

Intermediates:

4-[(6-Bromo-pyridine-2-carbonyl)-amino]-1-methyl-1H-pyrazole-3-carboxylicacid methyl ester

A mixture of 6-Bromo-pyridine-2-carboxylic acid (3000 mg; 14.85 mmol;1.00 eq.), 4-Amino-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester(2765 mg; 17.82 mmol; 1.20 eq.), Ethyl-diisopropyl-amine (6.57 mL; 37.13mmol; 2.50 eq.) and3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (4536 mg;17.82 mmol; 1.20 eq.) in DCM (20 mL) were stirred at RT for overnight.The reaction was filtered, the solid was washed with water, and thenacetonitile, the title compound was obtained as a white solid. Thefiltrate was washed with water, the organic layer was separated,concentrated, washed with methanol, and collected the title compound(combined portions: gave product 5000 mg, which was quantitative yield).LC-MS (M+1): 339/341.

4-{[6-(1-tert-Butoxycarbonyl-1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylicacid methyl ester

A reaction mixture of4-{[6-(1-tert-Butoxycarbonyl-1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylicacid methyl ester (5000 mg; 13.37 mmol),4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylicacid tert-butyl ester (4770 mg; 16.22 mmol; 1.10 eq.), dipotassiumcarbonate (2241 mg; 16.22 mmol; 1.10 eq.), 100 mL of dioxane and 10 mLof water was degassed. To it was added palladium; tritert-butylphosphane(376 mg; 0.74 mmol; 0.05 eq.), and the reaction was stirred at 35° C.overnight. The reaction was diluted with EA (100 mL), washed with brine,dried, and concentrated, white solid that precipitated out, filtered, toprovide the title compound (5700 mg, yield 90%). LC-MS (M+1): 427.

Lithium1-methyl-4-{[6-(1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-1H-pyrazole-3-carboxylate

A mixture of4-{[6-(1-tert-Butoxycarbonyl-1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylicacid methyl ester (2300 mg; 5.39 mmol; 1.00 eq.), lithium hydroxidehydrate (679 mg; 16.18 mmol; 3.00 eq.) in THF (13 mL) and water (13 mL)was stirred at RT overnight. The reaction was filtered and 1200 mg ofthe title compound was collected (yield 71%). LC-MS (M+1): 313.

6-(1H-Pyrazol-4-yl)-pyridine-2-carboxylic acid[3-(6-bromo-hexylcarbamoyl)-1-methyl-1H-pyrazol-4-yl]-amide

A mixture of lithium1-methyl-4-{[6-(1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-1H-pyrazole-3-carboxylate(100 mg; 0.31 mmol; 1.00 eq.), BOP (172 mg; 0.38 mmol; 1.20 eq.) andEthyl-diisopropyl-amine (0.16 mL; 0.94 mmol; 3.00 eq.) in DMF (2 mL),was stirred at RT for 10 min, cooled to 0° C., and 6-Bromo-hexylaminehydrochloride (2) (80 mg; 0.31 mmol; 1.00 eq.) was added. The reactionwas stirred for 3 hr at 0° C., quenched with water, and filtered, toprovide 80 mg of crude product, which was dried and used directly forthe next step. LC-MS (M+1): 475/477.

Example 8 16-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (3)

A mixture of 6-(1H-Pyrazol-4-yl)-pyridine-2-carboxylic acid[3-(6-bromo-hexylcarbamoyl)-1-methyl-1H-pyrazol-4-yl]-amide (80 mg; 0.17mmol; 1.00 eq.) and Cs₂CO₃ (82.42 mg; 0.25 mmol; 1.50 eq.) in DMA (10mL), was stirred at 70° C. for 1 hr. The solvent was removed and theresidue was purified by prep HPLC, providing the title compound. LC-MS(M+1): 394.

¹H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 9.21-9.03 (m, 1H), 8.72 (t,J=6.0 Hz, 1H), 8.31 (s, 1H), 8.11-7.96 (m, 2H), 7.85 (m, 2H), 4.20 (t,J=7.1 Hz, 2H), 3.95 (s, 3H), 2.12 (m, 2H), 1.67 (m, 5H), 1.50 (m, 2H).

Example 915-methyl-4,5,11,14,15,18,24-heptaazatetracyclo[18.3.1.1²,⁵.0¹³,¹ ⁷]pentacosa-1(23),2(25),3,13,16,20(24),21-heptaene-12,19-dione (2)

A mixture of 6-(1H-Pyrazol-4-yl)-pyridine-2-carboxylic acid[3-(5-bromo-pentylcarbamoyl)-1-methyl-1H-pyrazol-4-yl]-amide (73 mg;0.16 mmol; 1.00 eq.), sodium hydride (13 mg; 0.32 mmol; 2.00 eq.) in DMA(5 mL) was stirred at 60° C. for 1 hr. The solvent was removed and theresidue was purified by prep HPLC, providing the title compound. LC-MS(M+1): 380.

¹H NMR (400 MHz, Methanol-d4) δ 9.57 (s, 1H), 8.48 (s, 1H), 8.17 (s,1H), 7.99-8.01 (m, 2H), 7.92 (m, 2H), 4.42-4.51 (m, 2H), 4.0 (s, 3H),3.50 (m, 2H), 2.44 (m, 2H), 1.98-2.0 (m, 2H), 1.75-1.80 (m, 2H).

Example 104-methyl-4,5,10,13,14,17,23-heptaazatetracyclo[17.3.1.1²,⁵.0¹²,¹ ⁶]tetracosa-1(22),2(24),3,12,15,19(23),20-heptaene-11,18-dione (4)

A mixture of 6-(1H-Pyrazol-4-yl)-pyridine-2-carboxylic acid[3-(4-chloro-butylcarbamoyl)-1-methyl-1H-pyrazol-4-yl]-amide (90.00 mg;0.22 mmol; 1.00 eq.) and cesium (1+) carbonic acid (0.5) (109.46 mg;0.34 mmol; 1.50 eq.) in DMA (10 mL), was stirred at 70° C. for 1 hr. Themixture was purified by prep HPLC, providing the title compound. LC-MS(M+1): 366.

¹H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 12.36 (s, 1H), 8.57 (s, 2H),8.44 (s, 2H), 8.06-7.97 (m, 1H), 7.95 (dd, J=7.9, 1.2 Hz, 1H), 7.89 (dd,J=7.4, 1.1 Hz, 1H), 4.00 (d, J=6.7 Hz, 2H), 3.97 (s, 3H), 3.65 (t, J=6.8Hz, 2H), 1.97 (m, 2H), 1.92-1.80 (m, 2H).

Example 11 16-methyl-4,5,12,15,16,19-hexaazatetracyclo[19.3.1.1²,⁵.0¹ ⁴,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (1)

1-Methyl-4-[3-(1H-pyrazol-4-yl)-benzoylamino]-1H-pyrazole-3-carboxylicacid (6-bromo-hexyl)-amide (20.00 mg; 0.04 mmol; 1.00 eq.),Ethyl-diisopropyl-amine (0.01 mL; 0.08 mmol; 2.00 eq.) and DMA (3 mL)were charged in 10 mL microwave tube, and the reaction was placed in amicrowave at 100° C. for 20 min. The reaction was purified by prep HPLC,providing the title compound. LC-MS (M+1): 393.

¹H NMR (400 MHz, Methanol-d4) δ 11.58 (s, 1H), 8.24 (d, J=5.9 Hz, 2H),8.07 (s, 1H), 7.88-7.70 (m, 3H), 7.57 (t, J=7.7 Hz, 1H), 4.37-4.26 (m,2H), 3.97 (s, 3H), 3.50-3.36 (m, 2H), 1.94 (m, 2H), 1.75 (q, J=6.9 Hz,2H), 1.60 (m, 4H).

Intermediates:

Methanesulfonic acid 6-tert-butoxycarbonylamino-hexyl ester

To a stirring solution of (6-Hydroxy-hexyl)-carbamic acid tert-butylester (5000 mg; 23 mmol; 1.00 eq.) in THF (60 mL) andEthyl-diisopropyl-amine (5.63 mL; 32.21 mmol; 1.40 eq.) was added dropwise Methanesulfonyl chloride (2.23 mL; 28.76 mmol; 1.25 eq.) at 0° C.The reaction was stirred for 30 min at 0° C., then raised to RT for 1 h.EA (100 mL) was added, the organic layer was washed with brine, dried,and concentrated to provide a yellow solid (quantitative yield), whichwas directly used for the next step reaction. LC-MS (M+1): 296.

6-[1-(6-tert-Butoxycarbonylamino-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylicacid methyl

A mixture of 6-(1H-Pyrazol-4-yl)-pyridine-2-carboxylic acid methyl ester(1210 mg; 5.95 mmol; 1.00 eq.) in DMF (10 mL) was cooled to 0° C., andto it was added sodium hydride (476 mg; 11.91 mmol; 2.00 eq.). Thereaction was stirred for 30 min, then Methanesulfonic acid6-tert-butoxycarbonylamino-hexyl ester (2287 mg; 7.74 mmol; 1.30 eq.)was added. The mixture was stirred at RT for 3 hr, the solvent wasremoved and the residue was extracted with EA (30 mL×3). The organiclayer was washed with brine, the solvent was removed, and the residuewas purified by SNAP column to afford the title compound (480 mg, yield20%). LC-MS (M+1): 403.

Lithium6-[1-(6-tert-Butoxycarbonylamino-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylate

A mixture of6-[1-(6-tert-Butoxycarbonylamino-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylicacid methyl ester (347 mg; 0.86 mmol; 1.00 eq.), lithium hydroxidehydrate (72 mg; 1.72 mmol; 2.00 eq.) in THF (2 mL), and water (2 mL) wasstirred at RT for 2 hr. The solvent was removed, provided a white solidas desired, which was directly used for the next. LC-MS (M+1): 389.

4-({6-[1-(6-Amino-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester

To a stirred mixture of lithium6-[1-(6-tert-Butoxycarbonylamino-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylate(172 mg; 0.44 mmol; 1.00 eq.),3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (133 mg;0.52 mmol; 1.20 eq.) in DMF (3 mL), was added Ethyl-diisopropyl-amine(0.16 mL; 0.92 mmol; 2.10 eq.). The reaction was stirred for 30 min andthen 4-Amino-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylic acidmethyl ester (108 mg; 0.48 mmol; 1.10 eq.) was added. Stirring wascontinued overnight at RT, diluted with water (20 mL), extracted withDCM (40 mL×2), and the organic layer was washed with brine. The solventwas removed, got residue, provided4-({6-[1-(6-tert-Butoxycarbonylamino-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester (100 mg, yield 38.5%). LC-MS (M+1): 596. To the aboveproduct added methanol (1 mL), then hydrogen chloride (0.65 mL; 2.62mmol; 6.00 eq.), the reaction mixture was stirred at RT for overnight.The solvent was removed, and the residue was purified by prep HPLC(basic) (20-70% water in acetonitrile), providing the title compound (65mg, yield 27.8%). LC-MS (M+1): 496.

Lithium4-({6-[1-(6-Amino-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylate

A mixture of4-({6-[1-(6-Amino-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester (65 mg; 0.13 mmol; 1.00 eq.), lithium hydroxidehydrate (11 mg; 0.26 mmol; 2.00 eq.) in THF (2 mL) and water (2 mL) wasstirred at RT for 1 hr. The solvent was removed providing an off-whitesolid as desired, which was directly used for the next step reaction.LC-MS (M+1): 482.

Example 1216-(oxan-4-yl)-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹ ⁴ ,¹⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (12)

A mixture of lithium4-({6-[1-(6-Amino-hexyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylate(60 mg; 0.12 mmol; 1.00 eq.), BOP (70 mg; 0.15 mmol; 1.25 eq.) andEthyl-diisopropyl-amine (0.04 mL; 0.25 mmol; 2.00 eq.) in DMF (8 mL),was stirred at RT for 3 hr. The reaction was purified by prep HPLC(basic), providing the title compound (12 mg). LC-MS (M+1): 464.

¹H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 9.14 (s, 1H), 8.64 (t, J=5.9Hz, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 8.02 (t, J=7.7 Hz, 1H), 7.89-7.74(m, 2H), 4.65-4.47 (m, 1H), 4.21 (t, J=7.1 Hz, 2H), 4.07-3.88 (m, 3H),3.54-3.41 (m, 2H), 3.30-3.21 (2H), 2.24-1.96 (m, 5H), 1.71 (m, 4H), 1.51(q, J=6.5 Hz, 2H).

Example 13:15-(oxan-4-yl)-4,5,11,14,15,18-hexaazatetracyclo[18.3.1.1²,⁵.0¹³,¹ ⁷]pentacosa-1(23),2(25),3,13,16,20(24),21-heptaene-12,19-dione (6)3-[1-(5-tert-Butoxycarbonylamino-pentyl)-1H-pyrazol-4-yl]-benzoic acidmethyl ester

A mixture of 3-(1H-Pyrazol-4-yl)-benzoic acid methyl ester (1000 mg;4.95 mmol; 1.00 eq.), Methanesulfonic acid5-tert-butoxycarbonylamino-pentyl ester (1530 mg; 5.44 mmol; 1.10 eq.),and Cs₂CO₃ (2416 mg; 7.42 mmol; 1.50 eq.) in DMF (10 mL) was stirred at70° C. for 1 hr. The reaction was poured 60 mL of stirring water, awhite solid precipitated out, filtered, collected 1750 mg white solid astitle compound (yield 91.3%). LC-MS (M+1): 388.

Lithium3-[1-(5-tert-Butoxycarbonylamino-pentyl)-1H-pyrazol-4-yl]-benzoate

A reaction mixture of3-[1-(5-tert-Butoxycarbonylamino-pentyl)-1H-pyrazol-4-yl]-benzoic acidmethyl ester (1500 mg; 3.87 mmol; 1.00 eq.), lithium hydroxide hydrate(324 mg; 7.74 mmol; 2.00 eq.) in THF (8 mL) and water (8 mL) was stirredat RT for 2 hr, then at 40° C. for 3 hr. The mixture was added 10 mLwater and 10 mL EA. Separated off organic layer, aqueous layer wasevaporated off solvent, got residue, dried to provide the title compoundwhich was directly used for the next step reaction. LC-MS (M+1): 374.

4-{3-[1-(5-tert-Butoxycarbonylamino-pentyl)-1H-pyrazol-4-yl]-benzoylamino}-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester

A stirred solution of3-[1-(5-tert-Butoxycarbonylamino-pentyl)-1H-pyrazol-4-yl]-benzoic acidlithium (220.00 mg; 0.58 mmol; 1.00 eq.) and4-Amino-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylic acid methylester (156.74 mg; 0.70 mmol; 1.20 eq.) in DCM 4 ml was addedEthyl-diisopropyl-amine (0.21 ml; 1.16 mmol; 2.00 eq.), then3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (177.15 mg;0.70 mmol; 1.20 eq.), the reaction mixture was stirred at RT for 3 h,lc-ms showed clean desired. Diluted with EA, washed with brine, sodiumbicarbonate solution, brine, 10% citric acid aq, then brine, dried overMgSO₄ and concentrated to give the desired product.4-{3-[1-(5-tert-Butoxycarbonylamino-pentyl)-1H-pyrazol-4-yl]-benzoylamino}-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester. LC-MS (M+1): 581

Lithium4-{3-[1-(5-Amino-pentyl)-1H-pyrazol-4-yl]-benzoylamino}-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylate

To A solution of 4-{3-[1-(5-tert-Butoxycarbonylamino-pentyl)-1H-p4-{3-[1-(5-Amino-pentyl)-1H-pyrazol-4-yl]-benzoylamino}-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methylesteryrazol-4-yl]-benzoylamino}-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester (300.00 mg; 0.52 mmol; 1.00 eq.) in methanol 2 mladded hydrogen chloride (1.29 ml; 5.17 mmol; 10.00 eq.), stirred at RTfor 3 hr, reaction was completed, purified by basic HPLC, collected4-{3-[1-(5-Amino-pentyl)-1H-pyrazol-4-yl]-benzoylamino}-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester. LC-MS (M+1): 481

A mixture of4-{3-[1-(5-Amino-pentyl)-1H-pyrazol-4-yl]-benzoylamino}-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester (100.00 mg; 0.21 mmol; 1.00 eq.), lithium hydroxidehydrate (17.46 mg; 0.42 mmol; 2.00 eq.) in 1 ml THF and 1 ml water wasstirred at 40° C. for 2 hr, reaction was completed. Removed off solvent,got white solid as title compound. LC-MS (M+1): 467

15-(oxan-4-yl)-4,5,11,14,15,18-hexaazatetracyclo[18.3.1.1²,⁵.0¹³,¹ ⁷]pentacosa-1(23),2(25),3,13,16,20(24),21-heptaene-12,19-dione (6)

A mixture of lithium4-{3-[1-(5-Amino-pentyl)-1H-pyrazol-4-yl]-benzoylamino}-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylate(100 mg; 0.21 mmol; 1.00 eq.), BOP (115.81 mg; 0.25 mmol; 1.20 eq.) andEthyl-diisopropyl-amine (0.07 mL; 0.42 mmol; 2.00 eq.) in DMF (10 mL),was stirred at 0° C. for 3 hr. The solvent was removed and the residuewas purified by prep HPLC (basic, 20-70% acetonitrile in water),providing the title compound. LC-MS (M+1): 449.

1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.34 (s, 1H), 8.26-8.21 (m,1H), 7.90 (m, 2H), 7.70 (d, 1H)), 7.56 (d, 1H), 7.39 (t, J=7.7 Hz, 1H),4.55-4.50 (m, 1H), 4.24-4.20 (m, 2H), 4.02-3.90 (m, 2H), 3.53-3.48 (m,4H), 2.04-1.98 (m, 4H), 1.87-1.80 (m, 2H), 1.58-1.50 (m, 2H), 1.26-1.24(m, 2H).

Intermediates:

4-({6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxylicacid methyl ester

To a solution of1-Methyl-4-{[6-(1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-1H-pyrazole-3-carboxylicacid methyl ester (1200 mg; 3.68 mmol; 1.00 eq.) in DMF (15 mL) wasadded sodium hydride (176 mg; 7.35 mmol; 2.00 eq.). The reaction wasstirred at RT for 20 min, then 1-Bromo-2-chloro-ethane (0.46 mL; 5.52mmol; 1.50 eq.) was added, and result reaction mixture was stirred at RTovernight. The reaction was quenched with saturate ammonium chloride,then water (100 mL) was added. Solid precipitated out, filtered,collected white solid as the title compound (1200 mg, yield 84%). LC-MS(M+1): 389.

lithium4-({6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxylate

A mixture of4-({6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxylicacid methyl ester (1200 mg; 3.09 mmol; 1.00 eq.), lithium hydroxidehydrate (194 mg; 4.63 mmol; 1.50 eq.) in THF (4 mL) and water (4 mL),was stirred at 40° C. for 4 hr. The solvent was removed and the residuewas dried overnight in oven, provide white solid as the title compound(quantitative yield), which was directly used for the next step. LC-MS(M+1): 375.

6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid{1-methyl-3-[(morpholin-2-ylmethyl)-carbamoyl]-1H-pyrazol-4-yl}-amide

A reaction mixture of lithium4-({6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxylate(150 mg; 0.39 mmol; 1.00 eq.), BOP (220 mg; 0.48 mmol; 1.22 eq.),Ethyl-diisopropyl-amine (0.14 mL; 0.79 mmol; 2.00 eq.),2-Aminomethyl-morpholine-4-carboxylic acid tert-butyl ester (0.13 mL;0.47 mmol; 1.20 eq.), in DMF (10 mL) was stirred at RT for 2 hr. Thereaction was diluted with water, filtered, collected white off solid,which LC-MS showed desired. Above product was added hydrogen chloride(4.0M in dioxane) (0.98 mL; 3.94 mmol; 10.00 eq.) and methanol 1 mL, asresult reaction mixture was stirred at RT for 2 hr. removed off solventto provide a residue, which was dissolved in DMSO, and TEA was added toPH>=7. The compound was purified product by basic prep HPLC, providingthe title compound (90 mg, yield 48%). LC-MS (M+1): 373.

Example 1420-methyl-8,13-dioxa-4,5,10,16,19,20,23,29-octaazapentacyclo[23.3.1.1²,⁵.1¹⁰ ,¹ ⁴ .0¹ ⁸,²²]hentriaconta-1(28),2(31),3,18,21,25(29),26-heptaene-9,17,24-trione(8)

A mixture of6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid{1-methyl-3-[(morpholin-2-ylmethyl)-carbamoyl]-1H-pyrazol-4-yl}-amide(40 mg; 0.08 mmol; 1.00 eq.), Cs₂CO₃ (33 mg; 0.10 mmol; 1.20 eq.),potassium iodide (14 mg; 0.08 mmol; 1.00 eq.) and DMSO (4 mL) wascharged in sealed tube, was placed in a microwave at 110° C. for 60 min.The mixture was purified by basic prep HPLC to provide the titlecompound. LC-MS (M+1): 481.

1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.67 (s, 1H), 8.39 (d, J=5.4Hz, 2H), 8.21 (t, J=5.9 Hz, 1H), 8.04 (t, J=7.7 Hz, 1H), 7.98-7.84 (m,2H), 4.55 (t, J=5.6 Hz, 2H), 4.10 (m, 2H), 3.96 (s, 4H), 3.81-3.71 (m,1H), 3.58 (td, J=9.1, 8.5, 5.5 Hz, 1H), 3.44 (td, J=10.3, 3.9 Hz, 1H),2.84 (dd, J=12.3, 2.5 Hz, 1H), 2.65 (dd, J=9.6, 3.1 Hz, 2H), 2.43 (dd,J=12.3, 9.8 Hz, 1H).

Example 1518-methyl-11-oxa-4,5,8,14,17,18,21,27-octaazapentacyclo[21.3.1.1²,⁵.1⁸,¹².0¹⁶ ,² ⁰ ]nonacosa-1(26),2(29),3,16,19,23(27),24-heptaene-15,22-dione (7)

A mixture of6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid{1-methyl-3-[(morpholin-2-ylmethyl)-carbamoyl]-1H-pyrazol-4-yl}-amide(40.00 mg; 0.08 mmol; 1.00 eq.), Ethyl-diisopropyl-amine (0.02 mL; 0.10mmol; 1.20 eq.) and potassium iodide (14.04 mg; 0.08 mmol; 1.00 eq.) inDMSO (4 mL) were added to a sealed tube, which was placed in a microwaveat 110° C. for 60 min, still had starting material, then at 120° C. foranother 60 min. The reaction was purified by HPLC, providing the titlecompound. LC-MS (M+1): 437.

¹H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 9.05 (t, J=5.3 Hz, 1H), 8.57(s, 1H), 8.33 (s, 1H), 8.15 (d, J=0.6 Hz, 1H), 8.07-7.97 (m, 1H), 7.90(m, 2H), 4.65 (t, J=13.1 Hz, 1H), 4.33-4.20 (m, 1H), 3.95 (s, 3H), 3.80(d, J=11.2 Hz, 1H), 3.71 (d, J=11.0 Hz, 2H), 3.53-3.35 (m, 3H), 2.98 (m,2H), 2.44 (d, J=13.1 Hz, 1H), 2.24-2.04 (m, 1H), 1.96-1.69 (m, 1H).

Example 1610,17-dimethyl-8-oxa-4,5,10,13,16,17,20,26-octaazatetracyclo[20.3.1.1²,⁵.0¹⁵ ,¹ ⁹ ]heptacosa-1(25),2(27),3,15,18,22(26),23-heptaene-9,14,21-trione(5) 6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid[1-methyl-3-(2-methylamino-ethylcarbamoyl)-1H-pyrazol-4-yl]-amide

A mixture of lithium4-({6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxylate(150 mg; 0.39 mmol; 1.00 eq.), BOP (220 mg; 0.47 mmol; 1.20 eq.),(2-Amino-ethyl)-methyl-carbamic acid tert-butyl ester (82 mg; 0.48 mmol;1.22 eq.) and Ethyl-diisopropyl-amine (0.14 mL; 0.79 mmol; 2.00 eq.) inDMF (1.5 mL), was stirred at RT for 2 hr. The reaction was diluted withwater, extracted with DCM, washed with brine, dried over MgSO₄,evaporated off solvent, provide a residue as crude(2-{[4-({6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carbonyl]-amino}-ethyl)-methyl-carbamicacid tert-butyl ester. To above product added 1 mL methanol, thenhydrogen chloride (4.0M in dioxane) (0.98 mL; 3.94 mmol; 10.00 eq.), themixture was stirred at RT overnight. Filtered, collected solid, thissolid was placed in 2 mL of 10% Na₂CO₃ aq, stirred at RT for 10 min.filtered again, got white solid as the title compound (55 mg, yield32%). LC-MS (M+1): 431.

10,17-dimethyl-8-oxa-4,5,10,13,16,17,20,26-octaazatetracyclo[20.3.1.1²,⁵.0¹⁵ ,¹ ⁹ ]heptacosa-1(25),2(27),3,15,18,22(26),23-heptaene-9,14,21-trione(5)

A mixture of6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid[1-methyl-3-(2-methylamino-ethylcarbamoyl)-1H-pyrazol-4-yl]-amide (51mg; 0.12 mmol; 1.00 eq.), Cs₂CO₃ (38 mg; 0.12 mmol; 1.00 eq.), potassiumiodide (20 mg; 0.12 mmol; 1.00 eq.) and DMSO (5 mL) were added to asealed tube and was placed in a microwave at 110° C. for 60 min. Thereaction was purified by prep HPLC to afford the title compound. LC-MS(M+1): 439.

¹H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.97 (s, 1H), 8.51 (s, 1H),8.40 (s, 1H), 8.23 (t, J=6.0 Hz, 1H), 8.08 (t, J=7.7 Hz, 1H), 7.99-7.90(m, 2H), 7.31 (dd, J=15.6, 8.9 Hz, 1H), 3.96 (s, 3H), 3.53-3.37 (m, 6H),2.69 (t, J=6.4 Hz, 2H), 2.32 (s, 3H).

Example 178,15-dimethyl-4,5,8,11,14,15,18,24-octaazatetracyclo[18.3.1.1²,⁵.0¹³,¹ ⁷]pentacosa-1(23),2(25),3,13,16,20(24),21-heptaene-12,19-dione (10)

A mixture of6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid[1-methyl-3-(2-methylamino-ethylcarbamoyl)-1H-pyrazol-4-yl]-amide (50mg; 0.12 mmol; 1.00 eq.), Ethyl-diisopropyl-amine (0.03 mL; 0.17 mmol;1.50 eq.), potassium iodide (19 mg; 0.12 mmol; 1.00 eq.) and DMSO (5 mL)were added to a sealed tube, then placed in a microwave at 125° C. for60 min., 130° C. for another 60 min. reaction mixture was isolated byprep HPLC, providing the title compound. LC-MS (M+1): 395.

¹H NMR (500 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.23 (s, 1H), 8.75 (t, J=5.8Hz, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.99 (t, J=7.8 Hz, 1H), 7.87 (d,J=7.8 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 4.40-4.23 (m, 2H), 3.93 (s, 3H),3.42 (q, J=5.7 Hz, 4H), 3.03 (t, J=5.1 Hz, 2H), 2.14 (s, 3H).

Example 188,16-dimethyl-4,5,8,12,15,16,19,25-octaazatetracyclo[19.3.1.1²,⁵.0¹ ⁴ ,¹⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (11)

A mixture of6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid[1-methyl-3-(3-methylamino-propylcarbamoyl)-1H-pyrazol-4-yl]-amide (40mg; 0.09 mmol; 1.00 eq.), Ethyl-diisopropyl-amine (0.02 mL; 0.11 mmol;1.20 eq.), potassium iodide (15 mg; 0.09 mmol; 1.00 eq.) and DMSO (4 mL)were added to a sealed tube, then placed in a microwave at 130° C. for60 min. The reaction mixture was isolated by HPLC, providing the titlecompound.

1H NMR (500 MHz, DMSO-d6) δ 12.93 (s, 1H), 9.43 (s, 1H), 8.81 (t, J=5.9Hz, 1H), 8.27 (s, 1H), 8.10-7.93 (m, 2H), 7.83 (dd, J=35.7, 7.7 Hz, 2H),4.43-4.17 (m, 2H), 3.94 (s, 3H), 3.37 (dt, J=11.2, 6.0 Hz, 2H),3.00-2.80 (m, 2H), 2.44 (t, J=6.1 Hz, 2H), 2.21 (s, 3H), 1.77 (dq,J=11.8, 6.2 Hz, 2H).

Example 1917-methyl-4,5,8,13,16,17,20,26-octaazapentacyclo[20.3.1.1²,⁵.1⁸,¹¹.0¹ ⁵,¹ ⁹ ]octacosa-1(25),2(28),3,15,18,22(26),23-heptaene-14,21-dione (9)6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid{1-methyl-3-[(pyrrolidin-3-ylmethyl)-carbamoyl]-1H-pyrazol-4-yl}-amide

A mixture of lithium4-({6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxylate(150 mg; 0.39 mmol; 1.00 eq.), BOP (220 mg; 0.48 mmol; 1.22 eq.),Ethyl-diisopropyl-amine (0.14 mL; 0.79 mmol; 2.00 eq.), and3-Aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (95 mg;0.47 mmol; 1.20 eq.) in DMF (2 mL) was stirred at RT for 2 hr. Thereaction mixture was diluted with water, solid precipitated out,filtered, collected product, which was added hydrogen chloride (0.98 mL;3.94 mmol; 10.00 eq.), 1 mL methanol, and stirred at RT for 2 hr.removed off solvent, got residue, purified by basic prep HPLC, providingthe title compound. LC-MS (M+1): 457.

17-methyl-4,5,8,13,16,17,20,26-octaazapentacyclo[20.3.1.1²,⁵.1⁸,¹¹.0¹ ⁵,¹ ⁹ ]octacosa-1(25),2(28),3,15,18,22(26),23-heptaene-14,21-dione (9)

A mixture of6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid{1-methyl-3-[(pyrrolidin-3-ylmethyl)-carbamoyl]-1H-pyrazol-4-yl}-amide(60 mg; 0.13 mmol; 1.00 eq.), Ethyl-diisopropyl-amine (0.03 mL; 0.16mmol; 1.20 eq.), potassium iodide (22 mg; 0.13 mmol; 1.00 eq.) and DMSO(6 mL) were added to a sealed tube then placed tube in a microwave at125° C. for 2 hr. The reaction mixture was isolated by prep HPLC,providing the title compound. LC-MS (M+1): 421.

1H NMR (500 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.89 (s, 1H), 8.65 (dd,J=7.6, 5.0 Hz, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.98 (t, J=7.7 Hz, 1H),7.90 (d, J=7.7 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 4.37-4.21 (m, 2H), 3.93(s, 3H), 3.86-3.73 (m, 1H), 3.26-3.13 (m, 2H), 3.12-3.01 (m, 1H), 2.81(dd, J=14.0, 5.5 Hz, 2H), 2.24 (m, 2H), 2.14-2.00 (m, 1H), 1.91 (dt,J=8.2, 3.8 Hz, 1H), 1.45-1.33 (m, 1H).

Example 2026-hydroxy-6-methyl-22-oxa-2,5,6,9,18,19,24,30-octaazapentacyclo[22.2.2.1¹¹,¹⁵ .1¹ ⁶ ,¹ ⁹.0⁴,⁸]triaconta-4,7,11(30),12,14,16(29),17-heptaene-3,10,23-trione (21)6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid[3-((R)-3-hydroxy-piperidin-4-ylcarbamoyl)-1-methyl-1H-pyrazol-4-yl]-amide

A mixture of lithium4-({6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxylate(223 mg; 0.59 mmol; 1.00 eq.), HATU (245 mg; 0.64 mmol; 1.10 eq.) in DMF(4 mL), was stirred at RT for 15 min, and4-Amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (139 mg;0.64 mmol; 1.10 eq.) (trans racemic) was added. The mixture was stirredat RT for 2 hr, poured into water (20 mL), extracted with DCM (30 mL×3),separated, washed with brine (20 mL), dried, and the solvent wasremoved. To the residue added methanol (2 mL), then hydrogen chloride(4.0M in dioxane) (1.03 mL; 4.10 mmol; 7.00 eq.), and the mixture wasstirred at RT overnight. Another 1 mL of 4.0M HCl in dioxane was addedand stirred for another 3 hr. The solvent was removed and got whitesolid, which was dissolved in DMSO (5 mL), 1 mL TEA was added, and theresulting solution was subjected to prep HPLC to provide the titlecompound (110 mg, yield 40%). LC-MS (M+1): 473.

26-hydroxy-6-methyl-22-oxa-2,5,6,9,18,19,24,30-octaazapentacyclo[22.2.2.1¹¹,¹⁵ .1¹ ⁶ ,¹ ⁹.0⁴,⁸]triaconta-4,7,11(30),12,14,16(29),17-heptaene-3,10,23-trione (21)

A mixture of6-[1-(2-Chloro-ethyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid[3-((R)-3-hydroxy-piperidin-4-ylcarbamoyl)-1-methyl-1H-pyrazol-4-yl]-amide(50 mg; 0.11 mmol; 1.00 eq.), Cs₂CO₃ (45 mg; 0.14 mmol; 1.30 eq.),potassium iodide (17 mg; 0.11 mmol; 1.00 eq.) and DMSO (5 mL) were addedto a sealed tube, which was placed in a microwave at 110° C. for 60 min.The mixture was isolated by prep HPLC, providing the title compound (12mg, yield 23.6%). LC-MS (M+1): 437.

¹H NMR (400 MHz, DMSO-d6) δ 12.11 (d, J=38.0 Hz, 1H), 8.52 (d, J=6.2 Hz,1H), 8.39-8.18 (m, 3H), 8.06-7.79 (m, 3H), 5.23 (s, 1H), 5.04 (s, 1H),4.73 (s, 2H), 4.49 (s, 2H), 4.17 (d, J=14.7 Hz, 1H), 3.93 (s, 3H), 3.08(s, 1H), 2.40-2.27 (m, 3H), 1.69 (s, 1H).

Intermediates:

4-(3-Bromo-benzoylamino)-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester

A mixture of 3-Bromo-benzoic acid (1900 mg; 9.26 mmol; 1.00 eq.),Ethyl-diisopropyl-amine (3.61 mL; 20.38 mmol; 2.20 eq.), methyl4-amino-1-(tetrahydro-2h-pyran-4-yl)-1h-pyrazole-3-carboxylate (2190 mg;9.73 mmol; 1.05 eq.) and3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (2829 mg;11.12 mmol; 1.20 eq.) in DCM (100 mL) was stirred at RT for 3 hr. Thereaction mixture was washed with brine, dried over Na₂SO₄, and thesolvent was evaporated off, to provide the title compound as a whitesolid 3850 mg (quantitative yield). LC-MS (M+1): 408/410.

4-[3-(1-tert-Butoxycarbonyl-1H-pyrazol-4-yl)-benzoylamino]-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester

A mixture of4-(3-Bromo-benzoylamino)-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester (1889 mg; 4.63 mmol; 1.00 eq.),4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylicacid tert-butyl ester (1497 mg; 5.09 mmol; 1.10 eq.), dipotassiumcarbonate (703 mg; 5.09 mmol; 1.10 eq.) in dioxane (130 mL) and water(13 mL) was degassed, the added palladium; tritert-butylphosphane (118mg; 0.23 mmol; 0.05 eq.). The mixture was stirred at 40° C. for 24 hr,diluted with EA (100 mL), washed with brine (100 mL×2), dried overMgSO₄, evaporated off solvent to provide a residue, which was purifiedby SNAP column (100 g) (eluted with EA in hexane (20% to 80%). Collectedtitle compound (1500 mg, yield 65%). LC-MS (M+1): 496.

4-[3-(1H-Pyrazol-4-yl)-benzoylamino]-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester

To a solution of4-[3-(1-tert-Butoxycarbonyl-1H-pyrazol-4-yl)-benzoylamino]-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester (1500 mg; 3.03 mmol; 1.00 eq.) in methanol (5 mL) wasadded hydrogen chloride (6 mL; 24.22 mmol; 8.00 eq.), the mixture wasstirred for 4 hr at RT. The solvent was removed, providing a whitesolid, to which 10 mL of 5% Na₂CO₃ (aq) was added. The mixture wasstirred at RT for 30 min and filtered to give the title compound as awhite solid. LC-MS (M+1): 396.

4-{3-[1-(6-Amino-hexyl)-1H-pyrazol-4-yl]-benzoylamino}-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester

A mixture of4-[3-(1H-Pyrazol-4-yl)-benzoylamino]-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester (130 mg; 0.33 mmol; 1.00 eq.), Methanesulfonic acid6-tert-butoxycarbonylamino-hexyl ester (102 mg; 0.35 mmol; 1.05 eq.) anddipotassium carbonate (50 mg; 0.36 mmol; 1.10 eq.) in DMF (2 mL) wasstirred at 80° C. for 2 hr. The mixture was diluted with water,extracted with EA, the organic layer was washed with brine, dried, andthe solvent was removed. To the residue was added methanol (1 mL), andhydrogen chloride (4.0M in dioxane) (0.82 mL; 3.29 mmol; 10.00 eq.), andthe mixture was stirred at RT for overnight. The solvent was removed,the residue was dissolved in DMSO, neutralized with TEA, and purified byprep HPLC to provide the title compound. LC-MS (M+1): 495.

Lithium4-{3-[1-(6-Amino-hexyl)-1H-pyrazol-4-yl]-benzoylamino}-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylate

A mixture of4-{3-[1-(6-Amino-hexyl)-1H-pyrazol-4-yl]-benzoylamino}-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester (37 mg; 0.07 mmol; 1.00 eq.), lithium hydroxidehydrate (6.3 mg; 0.15 mmol; 2.00 eq.) in THF (1 mL) and water (1 mL) wasstirred at RT overnight. The solvent was removed and the residue wasdried and used directly in the next step. LC-MS (M+1): 481.

Example 2116-(oxan-4-yl)-4,5,12,15,16,19-hexaazatetracyclo[19.3.1.1²,⁵.0¹ ⁴ ,¹ ⁸]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (24)

To a mixture of lithium4-{3-[1-(6-Amino-hexyl)-1H-pyrazol-4-yl]-benzoylamino}-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylate(34 mg; 0.07 mmol; 1.00 eq.), Ethyl-diisopropyl-amine (0.01 mL; 0.08mmol; 1.20 eq.) in DMF (8 mL) was added(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(38 mg; 0.08 mmol; 1.20 eq.). The reaction was stirred at RT for 2 hr.The solvent was removed, and purified by prep HPLC to provide the titlecompound. LC-MS (M+1): 463.

¹H NMR (400 MHz, Methanol-d4) δ 8.30-8.20 (m, 2H), 8.17 (s, 1H),7.87-7.69 (m, 3H), 7.57 (t, J=7.7 Hz, 1H), 4.65-4.42 (m, 2H), 4.39-4.28(m2H), 4.16-4.03 (m, 2H), 3.61 (td, J=11.8, 2.4 Hz, 2H), 3.43 (t, J=7.2Hz, 2H), 2.27-2.03 (m, 3H), 1.95 (dt, J=11.5, 7.1 Hz, 2H), 1.85-1.70 (m,2H), 1.60 (dq, J=23.6, 7.9 Hz, 4H).

Example 2215-(oxan-4-yl)-8-oxa-4,5,11,14,15,18-hexaazatetracyclo[18.3.1.1²,⁵.0¹³,¹⁷ ]pentacosa-1(23),2(25),3,13,16,20(24),21-heptaene-12,19-dione (20)4-(3-{1-[2-(2-Amino-ethoxy)-ethyl]-1H-pyrazol-4-yl}-benzoylamino)-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester

A mixture of4-[3-(1H-Pyrazol-4-yl)-benzoylamino]-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester hydrochloride (3) (300 mg; 0.59 mmol; 1.00 eq.), andCs₂CO₃ (484 mg; 1.49 mmol; 2.50 eq.) in DMF (5 mL) was stirred at RT for30 min. To it added Methanesulfonic acid2-(2-tert-butoxycarbonylamino-ethoxy)-ethyl ester (185.23 mg; 0.65 mmol;1.10 eq.), and the reaction was heated at 80° C. stirring for 1 hr. Themixture was cooled, poured into water, extracted with EA (30 mL×3),dried over MgSO₄, evaporated off solvent to provide4-(3-{1-[2-(2-tert-Butoxycarbonylamino-ethoxy)-ethyl]-1H-pyrazol-4-yl}-benzoylamino)-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester. To the above product added methanol (2 mL), thenhydrogen chloride (4.0M in dioxane) (1.19 mL; 4.75 mmol; 8.00 eq.), asresulting mixture was stirred at RT for 3 hr. The solvent was removed toprovide a residue which was subjected to prep HPLC (basic) forisolation, affording the title compound (140 mg, yield 48.8%). LC-MS(M+1): 483.

Lithium4-(3-{1-[2-(2-Amino-ethoxy)-ethyl]-1H-pyrazol-4-yl}-benzoylamino)-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylate

A mixture of4-(3-{1-[2-(2-Amino-ethoxy)-ethyl]-1H-pyrazol-4-yl}-benzoylamino)-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester (142.00 mg; 0.29 mmol; 1.00 eq.), lithium hydroxidehydrate (24.70 mg; 0.59 mmol; 2.00 eq.) in THF (2 mL) and water (2 mL)was stirred at RT for 20 min. The solvent was removed and dried toprovide a white solid as the title compound, which was directly used inthe next step. LC-MS (M+1): 476.

15-(oxan-4-yl)-8-oxa-4,5,11,14,15,18-hexaazatetracyclo[18.3.1.1²,⁵.0¹³,¹⁷ ]pentacosa-1(23),2(25),3,13,16,20(24),21-heptaene-12,19-dione (20)

A mixture of lithium4-(3-{1-[2-(2-Amino-ethoxy)-ethyl]-1H-pyrazol-4-yl}-benzoylamino)-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylate(138 mg; 0.29 mmol; 1.00 eq.), BOP (159 mg; 0.35 mmol; 1.20 eq.) andEthyl-diisopropyl-amine (0.06 mL; 0.35 mmol; 1.20 eq.) in DMF (14 mL)was stirred at RT for 20 min. The solvent was removed, and the residuewas dissolved in DMSO, then subjected to prep HPLC to afford the titlecompound (28 mg, yield 21.8%). LC-MS (M+1): 451.

¹H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.21-8.09 (m, 2H), 7.89 (t,J=5.7 Hz, 1H), 7.86-7.76 (m, 2H), 7.57 (dt, J=7.7, 1.3 Hz, 1H), 7.40(dt, J=7.8, 1.5 Hz, 1H), 7.28 (t, J=7.7 Hz, 1H), 4.40-4.20 (m, 3H),4.00-3.89 (m, 2H), 3.85 (t, J=4.9 Hz, 2H), 3.58 (t, J=5.4 Hz, 2H),3.53-3.35 (m, 4H), 1.93 (m, 4H).

Intermediates:

6-(1H-Pyrazol-4-yl)-pyridine-2-carboxylic acid(1-methyl-3-pent-4-enylcarbamoyl-1H-pyrazol-4-yl)-amide

A mixture of lithium1-Methyl-4-{[6-(1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-1H-pyrazole-3-carboxylate(300.00 mg; 0.94 mmol; 1.00 eq.),(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(515.83 mg; 1.13 mmol; 1.20 eq.) And Ethyl-diisopropyl-amine (0.20 mL;1.13 mmol; 1.20 eq.) in DMF (4 mL) were stirred at RT for 20 min. Thesolvent was removed to afford a residue which was dissolved in DMSO andsubjected to prep HPLC to provide the title compound (158 mg, yield44%). LC-MS (M+1): 380.

6-(1-Allyl-1H-pyrazol-4-yl)-pyridine-2-carboxylic acid(1-methyl-3-pent-4-enylcarbamoyl-1H-pyrazol-4-yl)-amide

A mixture of 6-(1H-Pyrazol-4-yl)-pyridine-2-carboxylic acid(1-methyl-3-pent-4-enylcarbamoyl-1H-pyrazol-4-yl)-amide (150 mg; 0.40mmol; 1.00 eq.), 3-Bromo-propene (0.07 mL; 0.79 mmol; 2.00 eq.), andCs₂CO₃ (155 mg; 0.47 mmol; 1.20 eq.) were stirred at RT for 4 hr. Thereaction was quenched with aqueous NH₄Cl, then diluted with water, and awhite solid precipitated out, filtered to provide an off white solid astitle compound (120 mg, yield 72.4%). LC-MS (M+1): 420.

Example 23(7E)-16-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹ ⁴ ,¹⁸ ]hexacosa-1(24),2(26),3,7,14,17,21(25),22-octaene-13,20-dione (25)

To a solution of 6-(1-Allyl-1H-pyrazol-4-yl)-pyridine-2-carboxylic acid(1-methyl-3-pent-4-enylcarbamoyl-1H-pyrazol-4-yl)-amide (60 mg; 0.14mmol; 1.00 eq.) and DCM (10 mL) was addedbenzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-ruthenium;tricyclohexylphosphane (24 mg; 0.03 mmol; 0.20 eq.). The mixture wasstirred at 40° C. for 2 days. The solvent was removed and the residuewas purified by prep HPLC to afford the title compound. LC-MS (M+1):392.

¹H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.95 (s, 1H), 8.73 (d, J=5.8Hz, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 8.08-7.97 (m, 1H), 7.93 (s, 1H),7.81 (d, J=7.5 Hz, 1H), 6.33 (d, J=15.3 Hz, 1H), 5.87 (dd, J=15.2, 7.6Hz, 1H), 4.80 (d, J=7.0 Hz, 2H), 3.93 (s, 3H), 2.10 (s, 2H), 1.73 (s,2H), 2.41-2.28 (m, 2H).

Intermediates:

6-[1-(3-Chloro-propyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acidmethyl ester

A mixture of 6-(1H-Pyrazol-4-yl)-pyridine-2-carboxylic acid methyl ester(500.00 mg; 2.46 mmol; 1.00 eq.), 1-Bromo-3-chloro-propane (0.49 mL;4.92 mmol; 2.00 eq.) and Cs₂CO₃ (1603 mg; 2.95 mmol; 1.20 eq.) wasstirred at 80° C. for 20 min. The reaction was cooled, poured intowater, extracted with EA, washed with brine, dried over MgSO₄, andevaporated off solvent gave crude product, which was subjected to SNAPcolumn (25 g, eluted with 10%-80% EA in hexane) to provide the titleproduct (600 mg, yield 87%). LC-MS (M+1): 280.

6-{1-[3-(2-tert-Butoxycarbonylamino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carboxylicacid methyl ester

A mixture of (2-Mercapto-ethyl)-carbamic acid tert-butyl ester (0.29 mL;1.68 mmol; 1.30 eq.), Cs₂CO₃ (548 mg; 1.68 mmol; 1.30 eq.) and6-[1-(3-Chloro-propyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acidmethyl ester (362 mg; 1.29 mmol; 1.00 eq.) in DMF (3 mL) was stirred at60° C. for 3 hr. The reaction mixture was diluted with water, extractedwith EA, concentrated, got residue was purified by SNAP column (25 g,eluent with 20%-100% EA in hexane), providing the title compound (440mg, yield 80.8%). LC-MS (M+1): 421.

Lithium6-{1-[3-(2-tert-Butoxycarbonylamino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carboxylate

A mixture of6-{1-[3-(2-tert-Butoxycarbonylamino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carboxylicacid methyl ester (260 mg; 0.62 mmol; 1.00 eq.), lithium hydroxidehydrate (52 mg; 1.24 mmol; 2.00 eq.) in THF (2 mL) and water (2 mL) wasstirred at RT for 1 hr. The solvent was removed, dried in vacuum oven,providing a white solid which was directly used in the next step. LC-MS(M+1): 407.

4-[(6-{1-[3-(2-Amino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carbonyl)-amino]-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester

To a solution of6-{1-[3-(2-tert-Butoxycarbonylamino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carboxylicacid lithium (256 mg; 0.62 mmol; 1.00 eq.), Ethyl-diisopropyl-amine(0.23 mL; 1.30 mmol; 2.10 eq.) in DCM (6 mL), was added3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (189 mg;0.74 mmol; 1.20 eq.). The mixture were stirred for 15 min at RT, then4-Amino-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylic acid methylester (154 mg; 0.68 mmol; 1.10 eq.) was added, cintined stir at RT for24 hr. Additional BopCl (50 mg) and DIEPA 0.05 mL were added, stirredfor another 2 days. Water (5 mL) and DCM (30 mL) were added to thereaction solution, which was washed with 5 mL 5% NaHCO₃ (aq), thenbrine, the organic layer was separated out, dried over Na₂SO₄,evaporated off solvent, providing4-[(6-{1-[3-(2-tert-Butoxycarbonylamino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carbonyl)-amino]-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester as a residue. LC-MS (M+1): 614. To the above productwas added methanol (2 mL), then hydrogen chloride (1.24 mL; 4.96 mmol;8.00 eq.), the mixture was stirred at RT for overnight. The solvent wasremoved, providing an off white solid, which was added 3 mL 10% Na₂CO₃(aq), and mixture was stirred at RT for 30 min, filtered to provide 318mg of the title compound as a white solid (quantitative yield). LC-MS(M+1): 514.

Lithium4-[(6-{1-[3-(2-Amino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carbonyl)-amino]-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylate

A mixture of4-[(6-{1-[3-(2-Amino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carbonyl)-amino]-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylicacid methyl ester (308.17 mg; 0.60 mmol; 1.00 eq.), lithium hydroxidehydrate (50. mg; 1.20 mmol; 2.00 eq.) in THF (2 mL) and water (2 mL) wasstirred at RT overnight. The solvent was removed and dried to provide anoff white solid as title compound, which was directly used in the nextstep. LC-MS (M+1): 500.

Example 246-(oxan-4-yl)-9-thia-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (13)

A mixture of lithium4-[(6-{1-[3-(2-Amino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carbonyl)-amino]-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylate(303 mg; 0.60 mmol; 1.00 eq.),(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(328 mg; 0.72 mmol; 1.20 eq.) and Ethyl-diisopropyl-amine (0.13 mL; 0.72mmol; 1.20 eq.) in DMF (40 mL) were stirred at RT for 20 min. Thesolvent was removed and the residue was dissolved in DMSO, subjected toprep HPLC, providing the title compound (58 mg, yield 20%). LC-MS (M+1):482.

¹H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 9.19 (s, 1H), 8.81 (t, J=5.9Hz, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 8.03 (t, J=7.7 Hz, 1H), 7.91 (dd,J=7.9, 1.0 Hz, 1H), 7.83 (dd, J=7.5, 0.9 Hz, 1H), 4.56 (p, J=7.9 Hz,1H), 4.29 (t, J=7.4 Hz, 2H), 4.01 (m, 2H), 3.54-3.34 (m, 4H), 2.84-2.68(m, 4H), 2.51-2.40 (m, 2H), 2.05 (m, 4H).

Example 2516-(oxan-4-yl)-9λ⁴-thia-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-9,13,20-trione(14)

To a solution of6-{1-[3-(2-tert-Butoxycarbonylamino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carboxylicacid methyl ester (50 mg; 0.10 mmol; 1.00 eq.) in DCM (4 mL) was addedsodium hydrogen carbonate (45 mg; 0.54 mmol; 5.16 eq.). then3-chloroperbenzoic acid (29 mg; 0.12 mmol; 1.20 eq.), the mixture wasstirred at RT for 1 hr. removed off solvent, got residue was purified byprep HPLC providing the title compound. LC-MS (M+1): 498.

¹H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.96 (s, 1H), 8.82 (t, J=5.9Hz, 1H), 8.39 (s, 1H), 8.13 (s, 1H), 8.04 (t, J=7.7 Hz, 1H), 7.91 (dd,J=7.9, 1.0 Hz, 1H), 7.85 (dd, J=7.6, 0.9 Hz, 1H), 4.56 (q, J=8.0 Hz,1H), 4.40 (m, 2H), 3.99 (m, 2H), 3.85 (m, 2H), 3.59-3.37 (m, 2H), 3.19(m, 2H), 3.07-2.89 (m, 2H), 2.39 (m, 2H), 2.05 (m, 4H).

Example 2616-(oxan-4-yl)-9λ⁶-thia-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-9,9,13,20-tetrone (15)

To a solution of6-{1-[3-(2-tert-Butoxycarbonylamino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carboxylicacid methyl ester (50 mg; 0.10 mmol; 1.00 eq.) in DCM (4 mL) was addedsodium hydrogen carbonate (45 mg; 0.54 mmol; 5.16 eq.), Then3-chloroperbenzoic acid (29 mg; 0.12 mmol; 1.20 eq.), the mixture wasstirred at RT for 1 hr. removed off solvent, got residue was purified byprep HPLC providing the title compound. LC-MS (M+1): 514

¹H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 9.08 (s, 1H), 8.81 (t, J=5.8Hz, 1H), 8.41 (s, 1H), 8.18-7.96 (m, 2H), 7.88 (m, 2H), 4.65-4.46 (m,1H), 4.38 (t, J=7.4 Hz, 2H), 4.08-3.93 (m, 4H), 3.69 (dd, J=9.8, 5.4 Hz,2H), 3.49 (m, 6H), 2.06 (m, 4H).

Example 27(8Z)-16-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹ ⁴ ,¹⁸ ]hexacosa-1(24),2(26),3,8,14,17,21(25),22-octaene-13,20-dione (27)

The title compound was prepared in the same manner as Example 23,substituting compound 6-(1-Allyl-1H-pyrazol-4-yl)-pyridine-2-carboxylicacid (1-methyl-3-pent-4-enylcarbamoyl-1H-pyrazol-4-yl)-amide withcompound 6-(1-But-3-enyl-1H-pyrazol-4-yl)-pyridine-2-carboxylic acid(3-but-3-enylcarbamoyl-1-methyl-1H-pyrazol-4-yl)-amide in the last stepcyclization.

LC-MS (M+1): 392. ¹H NMR (400 MHz, Chloroform-d) δ 12.96 (s, 1H), 9.66(t, J=1.7 Hz, 1H), 8.20 (s, 1H), 7.97-7.83 (m, 2H), 7.61 (dd, J=7.6, 2.1Hz, 1H), 7.28 (d, J=1.9 Hz, 1H), 7.08 (s, 1H), 5.74-5.63 (m, 2H), 4.28(dt, J=8.8, 4.4 Hz, 2H), 3.96 (t, J=1.8 Hz, 3H), 3.43 (d, J=9.0 Hz, 2H),3.21-3.11 (m, 2H), 2.61 (d, J=9.3 Hz, 2H).

Example 28(8E)-16-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹ ⁴ ,¹⁸ ]hexacosa-1(24),2(26),3,8,14,17,21(25),22-octaene-13,20-dione (28)

The title compound (the geometric isomer of Example 27), was obtainedduring the preparation of Example 27. LC-MS (M+1): 392. ¹H NMR (400 MHz,Chloroform-d) δ 8.98 (d, J=0.7 Hz, 1H), 8.20 (s, 1H), 7.99-7.79 (m, 2H),7.61 (dd, J=7.6, 2.1 Hz, 1H), 7.28 (d, J=1.9 Hz, 1H), 7.08 (s, 1H)6.07-5.91 (m, 1H), 5.90-5.70 (m, 1H), 4.48-4.28 (m, 2H), 3.95 (s, 3H),3.51 (q, J=6.3 Hz, 2H), 2.58 (q, J=12.6, 8.8 Hz, 2H), 2.40 (q, J=6.6 Hz,2H).

Example 29(9E)-16-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹ ⁴ ,¹⁸ ]hexacosa-1(24),2(26),3,9,14,17,21(25),22-octaene-13,20-dione (29)

The title compound was prepared in the same manner as Example 23,substituting compound 6-(1-Allyl-1H-pyrazol-4-yl)-pyridine-2-carboxylicacid (1-methyl-3-pent-4-enylcarbamoyl-1H-pyrazol-4-yl)-amide withcompound of 6-(1-Pent-4-enyl-1H-pyrazol-4-yl)-pyridine-2-carboxylic acid(3-allylcarbamoyl-1-methyl-1H-pyrazol-4-yl)-amide in the last stepcyclization.

LC-MS (M+1): 392. 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.81-8.66(m, 2H), 8.29 (s, 1H), 8.15 (d, J=0.7 Hz, 1H), 8.07-7.95 (m, 1H), 7.90(dt, J=7.9, 2.1 Hz, 1H), 7.83 (dd, J=7.5, 1.0 Hz, 1H), 5.80 (d, J=15.5Hz, 1H), 5.61-5.48 (m, 1H), 4.28 (t, J=5.9 Hz, 2H), 3.99 (s, 3H), 2.65(s, 2H), 2.38-2.28 (m, 2H), 2.06-1.76 (m, 2H).

Example 30(9Z)-16-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹ ⁴ ,¹⁸ ]hexacosa-1(24),2(26),3,9,14,17,21(25),22-octaene-13,20-dione (30)

The title compound (the geometric isomer of Example 29), was obtainedduring the preparation of Example 29. LC-MS (M+1): 392. 1H NMR (400 MHz,DMSO-d6) δ 12.70 (s, 1H), 8.88 (s, 1H), 8.77 (t, J=6.1 Hz, 1H),8.37-8.22 (m, 1H), 8.11 (d, J=1.6 Hz, 1H), 8.02 (t, J=8.0 Hz, 1H),7.94-7.76 (m, 2H), 5.55 (dd, J=8.2, 4.4 Hz, 1H), 5.40 (t, J=9.0 Hz, 1H),4.28 (t, J=6.0 Hz, 2H), 3.96 (s, 3H), 3.89-3.68 (t, 2H), 2.77-2.56 (s,2H), 2.19-2.01 (m, 2H).

Example 319,10-dihydroxy-16-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (31)

To a stirring solution of Example 29 (30 mg; 0.08 mmol; 1.00 eq.) in amixture of acetone (2 mL) and water (0.2 ml), were added osmiumtetroxide (155 mg; 0.02 mmol, 2.5% in isopropanol); 0.20 eq.) and4-methylmorpholine n-oxide (17 mg; 0.15 mmol; 2.00 eq.). The mixture wasstirred at RT overnight, reaction was completed. After removal of thesolvents, the crude was purified by prep HPLC (20-80% ACN in water) toyield the title compound. LC-MS (M+1): 426. 1H NMR (400 MHz, DMSO-d6) δ12.73 (s, 1H), 9.11 (s, 1H), 8.64-8.53 (m, 1H), 8.32 (s, 1H), 8.15-7.94(m, 2H), 7.85-7.88 (m, 2H), 4.75 (s, 1H), 4.58 (m, 1H), 4.30 (s, 1H),4.16-4.05 (m, 2H), 3.96 (s, 3H), 3.70-3.71 (m, 1H), 3.68 (s, 1H).3.04-2.81 (m, 1H), 2.71-2.64 (m, 1H), 2.34-2.28 (m, 1H), 2.15-2.10 (m,1H), 1.90-1.84 (m, 1H).

Example 327,8-dihydroxy-16-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (32)

The title compound was prepared in the same manner as Example 31,substituting Example 29 with Example 23 for the oxidation reaction.LC-MS (M+1): 426.

¹H NMR (400 MHz, DMSO-d₆) δ 12.83 (s, 1H), 9.41 (d, J=2.8 Hz, 1H), 8.80(s, 1H), 8.32 (d, J=2.7 Hz, 1H), 8.08-7.98 (m, 2H), 7.85 (dt, J=28.5,4.9 Hz, 2H), 4.79 (s, 1H), 4.68 (d, J=7.6 Hz, 1H), 4.46 (d, J=6.5 Hz,1H), 4.33-4.17 (m, 2H), 3.95 (d, J=2.8 Hz, 3H), 3.89 (s, 1H), 3.56 (s,1H), 2.96 (s, 2H), 1.74 (d, J=12.2 Hz, 1H), 1.64 (s, 1H), 1.56-1.54 (m,2H).

Example 338,9-dihydroxy-16-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴ ,¹ ⁸ ]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaene-13,20-dione (33)

The title compound was prepared in the same manner as Example 31,substituting Example 29 with Example 28 for the oxidation reaction.LC-MS (M+1): 426. ¹H NMR (400 MHz, Methanol-d₄) δ 9.39 (s, 1H), 8.23 (d,J=3.1 Hz, 1H), 8.00-7.97 (m, 2H), 7.89 (d, J=7.1 Hz, 1H), 7.80 (d, J=7.8Hz, 1H), 4.51-4.49 (m, 1H), 4.35-4.30 (m, 1H), 4.05-4.01 (m, 1H), 3.98(s, 3H), 3.82 (d, J=7.6 Hz, 1H), 3.63-3.59 (m, 1H), 3.52 (s, 1H), 3.15(s, 1H), 2.67 (s, 2H), 2.36 (s, 1H), 2.05-1.92 (m, 2H).

Example 34(9E)-17-methyl-4,5,13,16,17,20,26-heptaazatetracyclo[20.3.1.1²,⁵.0¹ ⁵ ,¹⁹ ]heptacosa-1(25),2(27),3,9,15,18,22(26),23-octaene-14,21-dione (34)

The title compound was prepared in the same manner as Example 23,substituting compound 6-(1-Allyl-1H-pyrazol-4-yl)-pyridine-2-carboxylicacid (1-methyl-3-pent-4-enylcarbamoyl-1H-pyrazol-4-yl)-amide withcompound 6-(1-Pent-4-enyl-1H-pyrazol-4-yl)-pyridine-2-carboxylic acid(3-but-3-enylcarbamoyl-1-methyl-1H-pyrazol-4-yl)-amide in the last stepcyclization.

LC-MS (M+1): 406. 1H NMR (400 MHz, Chloroform-d) δ 12.69 (s, 1H), 9.0(s, 1H), 8.27 (s, 1H), 8.05-7.90 (m, 2H), 7.90-7.78 (m, 1H), 7.64 (dd,J=7.8, 1.7 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.06 (dt, J=14.9, 7.3 Hz,1H), 5.37 (dt, J=14.7, 6.7 Hz, 1H), 4.32 (d, J=7.2 Hz, 2H), 3.96 (s,3H). 3.61 (d, J=8.3 Hz, 2H), 3.38-3.30 (m, 1H), 2.59 (d, J=8.7 Hz, 1H),2.39 (dt, J=28.5, 8.0 Hz, 2H), 2.23-2.11 (m, 2H).

Example 3517-methyl-4,5,13,16,17,20,26-heptaazatetracyclo[20.3.1.1²,⁵.0¹ ⁵ ,¹ ⁹]heptacosa-1(25),2(27),3,15,18,22(26),23-heptaene-14,21-dione (35)

To a solution of Example 34 (15 mg) in a mixture of MeOH (5 ml) and EA(20 ml), was added 15 mg of 10% Pd/C wet. The mixture was put on parrshaker for 1 hr at 40 psi. The reaction mixture was filtered. The titlecompound was yielded as a white solid after the removal of the solvents.LC-MS (M+1): 408.

1H NMR (400 MHz, Chloroform-d) δ 12.44 (s, 1H), 8.81 (d, J=0.7 Hz, 1H),8.28 (s, 1H), 8.06-7.92 (m, 2H), 7.85 (t, J=7.8 Hz, 1H), 7.63 (dd,J=7.8, 1.0 Hz, 1H), 6.99 (t, J=6.9 Hz, 1H), 4.48-4.29 (m, 2H), 3.99 (s,3H), 3.56 (q, J=6.5 Hz, 2H), 2.03-1.83 (m, 2H), 1.76-1.61 (m, 4H),1.56-1.45 (m, 2H), 0.96-0.73 (m, 2H).

Example 369,10-dihydroxy-17-methyl-4,5,13,16,17,20,26-heptaazatetracyclo[20.3.1.1²,⁵.0¹⁵ ,¹ ⁹ ]heptacosa-1(25),2(27),3,15,18,22(26),23-heptaene-14,21-dione(36)

The title compound was prepared in the same manner as Example 31,substituting Example 29 with Example of 34. LC-MS (M+1): 439

¹H NMR (400 MHz, DMSO-d₆) δ 12.79 (s, 1H), 8.75 (d, J=8.5 Hz, 1H), 8.67(s, 1H), 8.63 (s, 1H), 8.36 (s, 1H), 8.20-8.15 (m, 1H), 7.93 (d, J=8.1Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 4.34-4.26 (m, 2H), 3.99 (s, 3H),3.75-3.70 (m, 2H), 2.75 (s, 1H), 2.42 (s, 1H). 2.20-2.03 (m, 2H),1.89-1.80 (m, 2H), 1.72-1.65 (m, 2H), 1.48-1.40 (m, 2H).

Example 37(7Z)-16-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹ ⁴ ,¹⁸ ]hexacosa-1(24),2(26),3,7,14,17,21(25),22-octaene-13,20-dione (37)

The title compound (the geometric isomer of Example 23) was yielded asthe minor product during the preparation of Example 23. LC-MS (M+1):392. 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.96 (s, 1H), 8.74 (t,J=6.1 Hz, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 8.01 (t, J=7.7 Hz, 1H), 7.93(d, J=7.8 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 6.34 (dt, J=14.5, 7.0 Hz,1H), 5.87 (dt, J=14.7, 6.9 Hz, 1H), 4.82 (d, J=7.0 Hz, 2H), 3.94 (s,3H), 3.42-3.27 (d, J=20.1 Hz, 2H), 2.17-2.05 (m, 2H), 1.81-1.68 (m, 2H).

Methanesulfonic acid 6-tert-butoxycarbonylamino-hex-2-ynyl ester

To a stirring solution of (6-hydroxy-hex-4-ynyl)-carbamic acidtert-butyl ester (100 mg; 0.47 mmol; 1.00 eq.) andethyl-diisopropyl-amine (0.12 ml; 0.70 mmol; 1.50 eq.) in THF (6.0 ml),was added methanesulfonyl chloride (0.05 ml; 0.59 mmol; 1.25 eq.)dropwise at rt and stirred for 2 h. The reaction mixture was dilutedwith EA, washed with brine, dried and concentrated to yield the crudetitle compound (136 mg; 0.47 mmol), which was used directly for the nextstep reaction. LC-MS (M+1): 292

4-({6-[1-(6-tert-Butoxycarbonylamino-hex-2-ynyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxylicacid methyl ester

A reaction mixture of cesium carbonate (304 mg; 0.93 mmol; 2.00 eq.) and1-methyl-4-{[6-(1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-1H-pyrazole-3-carboxylicacid methyl ester (152 mg; 0.47 mmol; 1.00 eq.) in DMF (1.0 ml) wasstirred at rt for 15 min. added methanesulfonic acid6-tert-butoxycarbonylamino-hex-2-ynyl ester (136 mg; 0.47 mmol; 1.00eq.). The resulting mixture was stirred at 60° C. for 2 h. The reactionmixture was poured into water, exacted with EtOAc and washed with brine,dried and concentrated to give the crude title compound (216 mg, yield89%), which was used directly for the next step reaction. LC-MS (M+1):522

4-({6-[1-(6-Amino-hex-2-ynyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxylicacid methyl ester

To a solution of the crude4-({6-[1-(6-tert-Butoxycarbonylamino-hex-2-ynyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxylicacid methyl ester (210 mg; 0.40 mmol; 1.00 eq.) in methanol (2.0 ml)added 4.0M HCl in dioxane hydrogen chloride (1.61 ml; 6.44 mmol; 16.00eq.) at rt, the mixture was stirred at rt for 2 h. The reaction mixturewas concentrated and purified by prep-HPLC (Waters, basic, 10-50% ACN inwater) to yield the title compound (96 mg; yield 57%). LC-MS (M+1): 422

Lithium4-({6-[1-(6-amino-hex-2-ynyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxylate

A mixture of4-({6-[1-(6-amino-hex-2-ynyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxylicacid methyl ester (94 mg; 0.22 mmol; 1.00 eq.) and lithium hydroxidehydrate (18 mg; 0.45 mmol; 2.00 eq.) in THF (2.00 ml) and water (2.00ml) was stirred at 40° C. for 1.5 h. The reaction mixture wasconcentrated to dryness to yield an off-white solid as the titlecompound. LC-MS (M+1): 407

Example 3816-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹ ⁴ ,¹ ⁸]hexacosa-1(24),2(26),3,14,17,21(25),22-heptaen-7-yne-13,20-dione (38)

A mixture of lithium4-({6-[1-(6-amino-hex-2-ynyl)-1H-pyrazol-4-yl]-pyridine-2-carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxylate(90 mg; 0.20 mmol; 1.00 eq.)(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(109.60 mg; 0.24 mmol; 1.20 eq.) and ethyl-diisopropyl-amine (0.07 ml;0.40 mmol; 2.00 eq.) in DMF (18.00 ml; 200 V) was stirred at rt for 1.5h. The reaction mixture was concentrated and the crude was purified byprep-HPLC (Waters, basic, 20-60% ACN in water) to yield the titlecompound as a white amorphous powder (15.00 mg; yield 19.2%). LC-MS(M+1): 390. 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 9.39 (s, 1H),8.67 (s, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 8.13-7.75 (m, 3H), 5.13 (s,2H), 3.97 (s, 3H), 3.59 (bs, 2H), 2.36 (bs, 2H), 1.71 (bs, 2H).

Example 39: Enzymatic Assays

IRAK4 Enzymatic Assay:

IRAK4 is a human purified recombinant enzyme (His-TEV-IRAK4 (1-460)).

In this assay, IRAK4 hydrolyses ATP, autophosphorylates andphosphorylates a Serine/Threonine generic peptidic substrate (STK:61ST1BLC from CisBio International). Measurement of IRAK-4 inhibition isperformed in 384-well format based on a luminescence assay (ADP-Glo™Kinase Assay from Promega). Purified human recombinant IRAK4 (0.3 μg/ml)and serial diluted compounds in DMSO (range of concentration from 10 μMto 0.5 nM) or controls (1% DMSO) are incubated for 15 minutes at RT inassay buffer containing 50 mM Hepes pH 7.0, Fatty acid-free BSA 0.1%,Dithiothreitol (DTT) 2 mM, MgCl2 10 mM, EGTA 0.5 mM, Triton X-100 0.01%,MnCl2 5 mM. The kinase reaction is then initiated by the addition of ATP(2 μM) and the peptidic substrate STK1-biotin peptide (300 nM). After 2hours of incubation at RT, the reaction is stopped and the unconsumedATP depleted by the addition of ADP-Glo™ Reagent according to supplierinstructions. After 40 minutes of incubation at RT, the Kinase DetectionReagent is then added to the assay plate according to supplierinstructions. After 20 minutes of incubation at RT, the luminescencesignal is measured with a plate-reading luminometer (PerkinElmerEnvision or equivalent reader).

IRAK1 Enzymatic Assay:

IRAK1 is a human purified recombinant enzyme (His-TEV-IRAK1 (194-712))

In this assay, IRAK1 hydrolyses ATP and autophosphorylates. Measurementof IRAK-1 inhibition is performed in 384-well format based onluminescence assay (ADP-Glo™ Kinase Assay from Promega). Purified humanrecombinant IRAK1 (0.3 μg/ml) and serial diluted compounds in DMSO(range of concentration from 10 μM to 0.5 nM) or controls (1% DMSO) areincubated for 15 minutes at RT in assay buffer containing 50 mM Hepes pH7.0, Fatty acid-free BSA 0.1%, Dithiothreitol (DTT) 2 mM, MgCl2 10 mM,EGTA 0.5 mM, Triton X-100 0.01%. The kinase reaction is then initiatedby the addition of ATP at a concentration of 1 μM. After 2 hours ofincubation at RT, the reaction is stopped and the unconsumed ATPdepleted by the addition of ADP-Glo™ Reagent according to supplierinstructions. After 40 minutes of incubation at RT, the Kinase DetectionReagent is then added to the assay plate according to supplierinstructions. After 20 minutes of incubation at RT, the luminescencesignal is measured with a luminometer (PerkinElmer Envision orequivalent reader).

Results are given in the following table.

IRAK1 IRAK4 Compound IC50 IC50 1 *** **** 2 *** *** 3 *** **** 4 ** ** 5**** **** 6 * * 7 ** **** 8 * *** 9 ** **** 10 ** *** 11 ** **** 12 ******* 13 *** **** 14 *** **** 15 *** **** 16 *** **** 17 *** **** 18 ******* 19 *** **** 20 * * 21 ** *** 22 *** **** 23 *** **** 24 *** **** 25**** **** 26 NT NT 27 *** **** 28 *** **** 29 *** **** 30 *** **** 31*** **** 32 *** **** 33 *** **** 34 *** **** 35 *** **** 36 *** **** 37*** **** 38 **** **** * IC₅₀ >5 μM ** IC₅₀ ranges from 1 μM-5 μM ***IC₅₀ ranges from 100 nM-1.0 μM **** IC₅₀ <100 nM NT Not Tested

Example 40. Pharmaceutical Preparations

(A) Injection vials: A solution of 100 g of an active ingredientaccording to the invention and 5 g of disodium hydrogen phosphate in 3 lof bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid,sterile filtered, transferred into injection vials, is lyophilized understerile conditions and is sealed under sterile conditions. Eachinjection vial contains 5 mg of active ingredient.

(B) Suppositories: A mixture of 20 g of an active ingredient accordingto the invention is melted with 100 g of soy lecithin and 1400 g ofcocoa butter, is poured into moulds and is allowed to cool. Eachsuppository contains 20 mg of active ingredient.

(C) Solution: A solution is prepared from 1 g of an active ingredientaccording to the invention, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g ofNa₂HPO₄.12 H₂O and 0.1 g of benzalkonium chloride in 940 mL ofbidistilled water. The pH is adjusted to 6.8, and the solution is madeup to 1 l and sterilized by irradiation. This solution could be used inthe form of eye drops.

(D) Ointment: 500 mg of an active ingredient according to the inventionis mixed with 99.5 g of Vaseline under aseptic conditions.

(E) Tablets: A mixture of 1 kg of an active ingredient according to theinvention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and0.1 kg of magnesium stearate is pressed to give tablets in aconventional manner in such a way that each tablet contains 10 mg ofactive ingredient.

(F) Coated tablets: Tablets are pressed analogously to Example E andsubsequently are coated in a conventional manner with a coating ofsucrose, potato starch, talc, tragacanth and dye.

(G) Capsules: 2 kg of an active ingredient according to the inventionare introduced into hard gelatin capsules in a conventional manner insuch a way that each capsule contains 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of an active ingredient according tothe invention in 60 l of bidistilled water is sterile filtered,transferred into ampoules, is lyophilized under sterile conditions andis sealed under sterile conditions. Each ampoule contains 10 mg ofactive ingredient.

(I) Inhalation spray: 14 g of an active ingredient according to theinvention are dissolved in 10 l of isotonic NaCl solution, and thesolution is transferred into commercially available spray containerswith a pump mechanism. The solution could be sprayed into the mouth ornose. One spray shot (about 0.1 mL) corresponds to a dose of about 0.14mg.

While a number of embodiments of this invention are described herein, itis apparent that the basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim:
 1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein: Ring A is a5-membered heterocylic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or a 5-membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; each of which is optionally substituted;Ring B is a 6-membered aryl, or a 6 membered monocyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur; each of which is optionally substituted; Ring C is a 5-memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-membered monocyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur; each of which is optionally substituted; X is absent, —CH═CH—,—C≡C—, —O—, —S—, —SO₂—, —SO—, —C(O)—, —CO₂—, —C(O)N(R)—, —OC(O)N(R)—,—NRC(O)—, —NRC(O)N(R)—, —NRSO₂—, or —N(R)—; Y is absent, a divalentC₃₋₁₀ aryl, a divalent 3-8 membered saturated or partially unsaturatedcarbocyclic ring, a divalent 3-7 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora divalent 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted; each R is independentlyhydrogen, C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 membered saturated orpartially unsaturated carbocyclic ring, a 3-7 membered heterocylic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted; or each R is independently—OR^(c), —SR^(c), —SO₂R^(c), —SOR^(c), —C(O)R^(c), —CO₂R^(c),—C(O)N(R)R^(c), —OC(O)N(R)R^(c), NRC(O)R^(c), —NRC(O)N(R)R^(c),—NRSO₂R^(c), or —N(R)R^(c); two R groups on the same atom are takentogether with the atom to which they are attached to form a C₃₋₁₀ aryl,a 3-8 membered saturated or partially unsaturated carbocyclic ring, a3-7 membered heterocylic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; each of which is optionally substituted;R^(a) is H or optionally substituted C₁₋₆ aliphatic; R^(b) is H oroptionally substituted C₁₋₆ aliphatic; each R^(c) is independently H oroptionally substituted C₁₋₆ aliphatic; n is 1, 2, 3, 4, or 5; p is 0, 1,2, 3, or 4; and r is 0, 1, or
 2. 2. The compound of claim 1, whereinRing A is imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, or 1,3,4-triazolyl;each of which is optionally substituted.
 3. The compound of claim 2,wherein Ring A is


4. The compound of claim 1, wherein Ring B is phenyl,2H,6H-1,5,2-dithiazinyl, pyrimidinyl, pyranyl, pyrazinyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, or triazinyl; each of which isoptionally substituted.
 5. The compound of claim 4, wherein Ring B isphenyl or pyridinyl.
 6. The compound of claim 1, wherein Ring C isimidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, or 1,3,4-triazolyl;each of which is optionally substituted.
 7. The compound of claim 6,wherein Ring C is pyrazolidinyl, pyrazolinyl, or pyrazolyl; each ofwhich is optionally substituted.
 8. The compound of claim 1, wherein Xis absent.
 9. The compound of claim 8, wherein X is —CH═CH—, —C≡C—, —O—,—S—, —SO₂—, —SO—, —CO₂—, —OC(O)N(Me)-, or —N(Me)-.
 10. The compound ofclaim 1, wherein Y is absent.
 11. The compound of claim 10, wherein Y isan optionally substituted divalent phenyl, naphthyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl,imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl,thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl.12. The compound of claim 1, of formula I-a,

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1, of formula I-d,

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, selected from Table 1


15. A pharmaceutical composition comprising a compound of claim 1, and apharmaceutically acceptable adjuvant, carrier, or vehicle.
 16. A methodfor inhibiting IRAK, or a mutant thereof, activity in a patient or in abiological sample, comprising the step of administering to said patientor contacting said biological sample with a compound of claim 1 or aphysiologically acceptable salt thereof.
 17. A method for treatingcancer in a subject, comprising the step of administering to saidsubject a compound of claim 1 or a physiologically acceptable saltthereof.
 18. A process for manufacturing a compound of formula Iaccording to claim 1, comprising the steps of: reacting a compound offormula (A):

wherein Ring A, Ring B, Ring C, X, Y, R, R^(a), R^(b), n, p, and r, areas defined in claim 1; with a ring closing agent to provide a compoundof formula I of claim
 1. 19. The compound of claim 2, wherein Ring A ispyrazolidinyl, pyrazolinyl, or pyrazolyl; each of which is optionallysubstituted.
 20. The compound of claim 4, wherein Ring B is


21. The compound of claim 7, wherein Ring C is


22. The compound of claim 11, wherein Y is an optionally substituteddivalent pyrrolidine, piperidine, or morpholine.
 23. The compound ofclaim 11, wherein Y is


24. The compound of claim 1, of formula I-b,

or a pharmaceutically acceptable salt thereof.
 25. The compound of claim1, of formula I-c,

or a pharmaceutically acceptable salt thereof.